id
stringlengths 7
8
| tokens
sequence | ner_tags
sequence | texts
stringlengths 31
3.46k
| input_ids
sequence | token_type_ids
sequence | attention_mask
sequence | labels
sequence |
---|---|---|---|---|---|---|---|
10739770 | [
"The",
"gene",
"for",
"May-Hegglin",
"anomaly",
"localizes",
"to",
"a",
"<1-Mb",
"region",
"on",
"chromosome",
"22q12.3-13.1.",
"The",
"May-Hegglin",
"anomaly",
"(MHA)",
"is",
"an",
"autosomal",
"dominant",
"platelet",
"disorder",
"of",
"unknown",
"etiology.",
"It",
"is",
"characterized",
"by",
"thrombocytopenia,",
"giant",
"platelets,",
"and",
"leukocyte",
"inclusion",
"bodies,",
"and",
"affected",
"heterozygotes",
"are",
"predisposed",
"to",
"bleeding",
"episodes.",
"The",
"MHA",
" ",
"gene",
"has",
"recently",
"been",
"localized,",
"by",
"means",
"of",
"linkage",
"analysis,",
"to",
"a",
"13.6-cM",
"region",
"on",
"chromosome",
"22,",
"and",
"the",
"complete",
"chromosome",
"22",
"sequence",
"has",
"been",
"reported.",
"We",
"recently",
"performed",
"a",
"genome",
"scan",
"for",
"the",
"MHA",
" ",
"gene",
"in",
"29",
"members",
"of",
"a",
"large,",
"multigenerational",
"Italian",
"family,",
"and",
"we",
"now",
"confirm",
"that",
"the",
"MHA",
" ",
"locus",
"is",
"on",
"chromosome",
"22q12.",
"3-13.1.",
"The",
"maximal",
"two-point",
"LOD",
"score",
"of",
"4.50",
"was",
"achieved",
"with",
"the",
"use",
"of",
"marker",
"D22S283,",
"at",
"a",
"recombination",
"fraction",
"of.05.",
"Haplotype",
"analysis",
"narrowed",
"the",
"MHA",
" ",
"critical",
"region",
"to",
"6.6",
"cM",
"between",
"markers",
"D22S683",
"and",
"D22S1177.",
"It",
"is",
"of",
"note",
"that",
"the",
"chromosome",
"22",
"sequence",
"allowed",
"all",
"markers",
"to",
"be",
"ordered",
"correctly,",
"identified",
"all",
"the",
"candidate",
"genes",
"and",
"predicted",
"genes,",
"and",
"specifically",
"determined",
"the",
"physical",
"size",
"of",
"the",
"MHA",
" ",
"region",
"to",
"be",
"0.",
"7",
"Mb.",
"These",
"results",
"significantly",
"narrow",
"the",
"region",
"in",
"which",
"the",
"MHA",
" ",
"gene",
"is",
"located,",
"and",
"they",
"represent",
"the",
"first",
"use",
"of",
"chromosome",
"22",
"data",
"to",
"positionally",
"clone",
"a",
"disease",
"gene."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The gene for May-Hegglin anomaly localizes to a <1-Mb region on chromosome 22q12.3-13.1. The May-Hegglin anomaly (MHA) is an autosomal dominant platelet disorder of unknown etiology. It is characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, and affected heterozygotes are predisposed to bleeding episodes. The MHA gene has recently been localized, by means of linkage analysis, to a 13.6-cM region on chromosome 22, and the complete chromosome 22 sequence has been reported. We recently performed a genome scan for the MHA gene in 29 members of a large, multigenerational Italian family, and we now confirm that the MHA locus is on chromosome 22q12. 3-13.1. The maximal two-point LOD score of 4.50 was achieved with the use of marker D22S283, at a recombination fraction of.05. Haplotype analysis narrowed the MHA critical region to 6.6 cM between markers D22S683 and D22S1177. It is of note that the chromosome 22 sequence allowed all markers to be ordered correctly, identified all the candidate genes and predicted genes, and specifically determined the physical size of the MHA region to be 0. 7 Mb. These results significantly narrow the region in which the MHA gene is located, and they represent the first use of chromosome 22 data to positionally clone a disease gene. | [
2,
1920,
2359,
1958,
2278,
17,
2234,
3312,
7782,
20950,
18440,
1942,
43,
32,
21,
17,
5667,
3031,
1990,
5597,
2950,
16886,
1028,
18,
23,
17,
2590,
18,
21,
18,
1920,
2278,
17,
2234,
3312,
7782,
20950,
12,
5146,
1019,
13,
1977,
1925,
13027,
6379,
7163,
4770,
1927,
5435,
10383,
18,
2176,
1977,
4378,
2007,
17100,
16,
15041,
10097,
16,
1930,
11864,
6125,
8322,
16,
1930,
4218,
22910,
2032,
23002,
1007,
1942,
7633,
9232,
18,
1920,
5146,
1019,
2359,
2258,
3998,
2252,
6579,
16,
2007,
4457,
1927,
8611,
2333,
16,
1942,
43,
2590,
18,
26,
17,
3195,
3031,
1990,
5597,
2950,
16,
1930,
1920,
4080,
5597,
2950,
3244,
2258,
2252,
2568,
18,
2038,
3998,
2593,
43,
3843,
4519,
1958,
1920,
5146,
1019,
2359,
1922,
3230,
4678,
1927,
43,
3103,
16,
2779,
14687,
5524,
21714,
15922,
3416,
16,
1930,
2038,
5195,
4763,
1988,
1920,
5146,
1019,
6730,
1977,
1990,
5597,
2950,
16886,
1028,
18,
23,
17,
2590,
18,
21,
18,
1920,
7275,
2288,
17,
3575,
15187,
3593,
1927,
24,
18,
2761,
1982,
5032,
1956,
1920,
2485,
1927,
4966,
8631,
24900,
4839,
1010,
16,
2019,
43,
7827,
3906,
1927,
18,
2914,
18,
10949,
2333,
8400,
1919,
1920,
5146,
1019,
4140,
3031,
1942,
26,
18,
26,
3195,
2192,
4432,
8631,
24900,
6735,
1010,
1930,
8631,
24900,
20032,
1027,
18,
2176,
1977,
1927,
4725,
1988,
1920,
5597,
2950,
3244,
5563,
2136,
4432,
1942,
1998,
12011,
10329,
16,
2899,
2136,
1920,
6610,
2628,
1930,
4396,
2628,
16,
1930,
4475,
3180,
1920,
3841,
3081,
1927,
1920,
5146,
1019,
3031,
1942,
1998,
20,
18,
27,
5667,
18,
2144,
2274,
2567,
8400,
1920,
3031,
1922,
2154,
1920,
5146,
1019,
2359,
1977,
4810,
16,
1930,
2611,
3015,
1920,
2561,
2485,
1927,
5597,
2950,
2230,
1942,
20172,
1954,
7842,
43,
2573,
2359,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
19718767 | [
"NR2E3",
" ",
"mutations",
"in",
"enhanced",
"S-cone",
"sensitivity",
"syndrome",
"(ESCS),",
"Goldmann-Favre",
"syndrome",
"(GFS),",
"clumped",
"pigmentary",
"retinal",
"degeneration",
"(CPRD),",
"and",
"retinitis",
"pigmentosa",
"(RP).",
"NR2E3",
",",
"also",
"called",
"photoreceptor-specific",
"nuclear",
"receptor",
" ",
"(",
"PNR",
"),",
"is",
"a",
"transcription",
"factor",
"of",
"the",
"nuclear",
"hormone",
"receptor",
"superfamily",
"whose",
"expression",
"is",
"uniquely",
"restricted",
"to",
"photoreceptors.",
"There,",
"its",
"physiological",
"activity",
"is",
"essential",
"for",
"proper",
"rod",
"and",
"cone",
"photoreceptor",
"development",
"and",
"maintenance.",
"Thirty-two",
"different",
"mutations",
"in",
"NR2E3",
" ",
"have",
"been",
"identified",
"in",
"either",
"homozygous",
"or",
"compound",
"heterozygous",
"state",
"in",
"the",
"recessively",
"inherited",
"enhanced",
"S-cone",
"sensitivity",
"syndrome",
"(ESCS),",
"Goldmann-Favre",
"syndrome",
"(GFS),",
"and",
"clumped",
"pigmentary",
"retinal",
"degeneration",
"(CPRD).",
"The",
"clinical",
"phenotype",
"common",
"to",
"all",
"these",
"patients",
"is",
"night",
"blindness,",
"rudimental",
"or",
"absent",
"rod",
"function,",
"and",
"hyperfunction",
"of",
"the",
"\"blue\"",
"S-cones.",
"A",
"single",
"p.G56R",
" ",
"mutation",
"is",
"inherited",
"in",
"a",
"dominant",
"manner",
"and",
"causes",
"retinitis",
"pigmentosa",
"(RP).",
"We",
"have",
"established",
"a",
"new",
"locus-specific",
"database",
"for",
"NR2E3",
" ",
"(www.LOVD.nl/eye),",
"containing",
"all",
"reported",
"mutations,",
"polymorphisms,",
"and",
"unclassified",
"sequence",
"variants,",
"including",
"novel",
"ones.",
"A",
"high",
"proportion",
"of",
"mutations",
"are",
"located",
"in",
"the",
"evolutionarily-conserved",
"DNA-binding",
"domains",
"(DBDs)",
"and",
"ligand-binding",
"domains",
"(LBDs)",
"of",
"NR2E3",
".",
"Based",
"on",
"homology",
"modeling",
"of",
"these",
"NR2E3",
" ",
"domains,",
"we",
"propose",
"a",
"structural",
"localization",
"of",
"mutated",
"residues.",
"The",
"high",
"variability",
"of",
"clinical",
"phenotypes",
"observed",
"in",
"patients",
"affected",
"by",
"NR2E3",
"-linked",
"retinal",
"degenerations",
"may",
"be",
"caused",
"by",
"different",
"disease",
"mechanisms,",
"including",
"absence",
"of",
"DNA-binding,",
"altered",
"interactions",
"with",
"transcriptional",
"coregulators,",
"and",
"differential",
"activity",
"of",
"modifier",
"genes."
] | [
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
2,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP). NR2E3 , also called photoreceptor-specific nuclear receptor ( PNR ), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3 . Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3 -linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes. | [
2,
5214,
1028,
24336,
3527,
1922,
4256,
61,
17,
11841,
3802,
4741,
12,
17854,
13,
16,
6557,
8890,
17,
5505,
1936,
4741,
12,
9281,
1036,
13,
16,
2111,
6807,
1919,
12905,
2141,
6943,
9174,
12,
15530,
1007,
13,
16,
1930,
7599,
3678,
12905,
5360,
12,
4822,
13,
18,
5214,
1028,
24336,
16,
2222,
6043,
16383,
17,
2487,
4254,
3148,
12,
7594,
1005,
13,
16,
1977,
43,
3213,
2991,
1927,
1920,
4254,
6365,
3148,
13975,
6098,
2294,
1977,
15764,
6715,
1942,
19102,
18,
2276,
16,
2496,
5005,
2455,
1977,
4415,
1958,
3405,
6275,
1930,
11841,
16383,
2740,
1930,
6291,
18,
9942,
17,
2288,
2413,
3527,
1922,
5214,
1028,
24336,
2162,
2252,
2899,
1922,
3108,
9419,
2014,
3547,
9589,
3360,
1922,
1920,
13992,
1954,
12911,
4256,
61,
17,
11841,
3802,
4741,
12,
17854,
13,
16,
6557,
8890,
17,
5505,
1936,
4741,
12,
9281,
1036,
13,
16,
1930,
2111,
6807,
1919,
12905,
2141,
6943,
9174,
12,
15530,
1007,
13,
18,
1920,
2535,
4629,
3059,
1942,
2136,
2144,
2132,
1977,
9609,
19880,
16,
21286,
12863,
2014,
7685,
6275,
2347,
16,
1930,
4194,
4916,
1927,
1920,
6,
4735,
6,
61,
17,
18506,
18,
43,
2957,
58,
18,
28845,
1016,
1005,
3979,
1977,
12911,
1922,
43,
6379,
5222,
1930,
5092,
7599,
3678,
12905,
5360,
12,
4822,
13,
18,
2038,
2162,
4379,
43,
2814,
6730,
17,
2487,
5039,
1958,
5214,
1028,
24336,
12,
6425,
18,
18412,
1007,
18,
9092,
19,
5723,
13,
16,
3165,
2136,
2568,
3527,
16,
8321,
16,
1930,
29562,
2828,
3244,
4936,
16,
2710,
4008,
8067,
18,
43,
2149,
4242,
1927,
3527,
2032,
4810,
1922,
1920,
18584,
17,
5305,
2678,
17,
2743,
4682,
12,
22565,
1036,
13,
1930,
5207,
17,
2743,
4682,
12,
22606,
1036,
13,
1927,
5214,
1028,
24336,
18,
2454,
1990,
9039,
7081,
1927,
2144,
5214,
1028,
24336,
4682,
16,
2038,
8040,
43,
4346,
5363,
1927,
8336,
4248,
18,
1920,
2149,
5687,
1927,
2535,
6568,
2528,
1922,
2132,
4218,
2007,
5214,
1028,
24336,
17,
4624,
6943,
9174,
1036,
2278,
1998,
4189,
2007,
2413,
2573,
3531,
16,
2710,
3905,
1927,
2678,
17,
2743,
16,
5520,
3719,
1956,
5224,
26648,
20219,
16,
1930,
5611,
2455,
1927,
22883,
2628,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
1,
2,
2,
2,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9452040 | [
"Novel",
"nonsense",
"mutation",
"in",
"exon",
"15",
"of",
"the",
"APC",
" ",
"gene",
"in",
"one",
"Jewish",
"family."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0
] | Novel nonsense mutation in exon 15 of the APC gene in one Jewish family. | [
2,
4008,
19605,
3979,
1922,
7049,
2461,
1927,
1920,
9187,
2359,
1922,
2340,
28296,
2471,
3416,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
-100
] |
7611281 | [
"Tyrosinase",
"inhibition",
"due",
"to",
"interaction",
"of",
"homocyst(e)ine",
"with",
"copper:",
"the",
"mechanism",
"for",
"reversible",
"hypopigmentation",
"in",
"homocystinuria",
"due",
"to",
"cystathionine",
"beta-synthase",
"deficiency.",
"Deficiency",
"of",
"cystathionine",
"beta-synthase",
"(CBS)",
"is",
"a",
"genetic",
"disorder",
"of",
"transsulfuration",
"resulting",
"in",
"elevated",
"plasma",
"homocyst(e)ine",
"and",
"methionine",
"and",
"decreased",
"cysteine.",
"Affected",
"patients",
"have",
"multisystem",
"involvement,",
"which",
"may",
"include",
"light",
"skin",
"and",
"hair.",
"Reversible",
"hypopigmentation",
"in",
"treated",
"homocystinuric",
"patients",
"has",
"been",
"infrequently",
"reported,",
"and",
"the",
"mechanism",
"is",
"undefined.",
"Two",
"CBS-deficient",
"homocystinuric",
"patients",
"manifested",
"darkening",
"of",
"their",
"hypopigmented",
"hair",
"following",
"treatment",
"that",
"decreased",
"plasma",
"homocyst(e)ine.",
"We",
"hypothesized",
"that",
"homocyst(e)ine",
"inhibits",
"tyrosinase,",
"the",
"major",
"pigment",
"enzyme.",
"The",
"activity",
"of",
"tyrosinase",
"extracted",
"from",
"pigmented",
"human",
"melanoma",
"cells",
"(MNT-1)",
"that",
"were",
"grown",
"in",
"the",
"presence",
"of",
"homocysteine",
"was",
"reduced",
"in",
"comparison",
"to",
"that",
"extracted",
"from",
"cells",
"grown",
"without",
"homocysteine.",
"Copper",
"sulfate",
"restored",
"homocyst(e)ine-inhibited",
"tyrosinase",
"activity",
"when",
"added",
"to",
"the",
"culture",
"cell",
"media",
"at",
"a",
"proportion",
"of",
"1.25",
"mol",
"of",
"copper",
"sulfate",
"per",
"1",
"mol",
"of",
"DL-homocysteine.",
"Holo-tyrosinase",
"activity",
"was",
"inhibited",
"by",
"adding",
"DL-homocysteine",
"to",
"the",
"assay",
"reaction",
"mixture,",
"and",
"the",
"addition",
"of",
"copper",
"sulfate",
"to",
"the",
"reaction",
"mixture",
"prevented",
"this",
"inhibition.",
"Other",
"tested",
"compounds,",
"L-cystine",
"and",
"betaine",
"did",
"not",
"affect",
"tyrosinase",
"activity.",
"Our",
"data",
"suggest",
"that",
"reversible",
"hypopigmentation",
"in",
"homocystinuria",
"is",
"the",
"result",
"of",
"tyrosinase",
"inhibition",
"by",
"homocyst(e)ine",
"and",
"that",
"the",
"probable",
"mechanism",
"of",
"this",
"inhibition",
"is",
"the",
"interaction",
"of",
"homocyst(e)ine",
"with",
"copper",
"at",
"the",
"active",
"site",
"of",
"tyrosinase."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency. Deficiency of cystathionine beta-synthase (CBS) is a genetic disorder of transsulfuration resulting in elevated plasma homocyst(e)ine and methionine and decreased cysteine. Affected patients have multisystem involvement, which may include light skin and hair. Reversible hypopigmentation in treated homocystinuric patients has been infrequently reported, and the mechanism is undefined. Two CBS-deficient homocystinuric patients manifested darkening of their hypopigmented hair following treatment that decreased plasma homocyst(e)ine. We hypothesized that homocyst(e)ine inhibits tyrosinase, the major pigment enzyme. The activity of tyrosinase extracted from pigmented human melanoma cells (MNT-1) that were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfate restored homocyst(e)ine-inhibited tyrosinase activity when added to the culture cell media at a proportion of 1.25 mol of copper sulfate per 1 mol of DL-homocysteine. Holo-tyrosinase activity was inhibited by adding DL-homocysteine to the assay reaction mixture, and the addition of copper sulfate to the reaction mixture prevented this inhibition. Other tested compounds, L-cystine and betaine did not affect tyrosinase activity. Our data suggest that reversible hypopigmentation in homocystinuria is the result of tyrosinase inhibition by homocyst(e)ine and that the probable mechanism of this inhibition is the interaction of homocyst(e)ine with copper at the active site of tyrosinase. | [
2,
27083,
3523,
2810,
1942,
2835,
1927,
16350,
23159,
1031,
12,
47,
13,
11116,
1956,
9541,
30,
1920,
2856,
1958,
10743,
26497,
29043,
18326,
1922,
16350,
23159,
2268,
8754,
2810,
1942,
9446,
2183,
11215,
4666,
17,
8921,
6179,
18,
6179,
1927,
9446,
2183,
11215,
4666,
17,
8921,
12,
16341,
13,
1977,
43,
3299,
4770,
1927,
2127,
19028,
4806,
3864,
1922,
4664,
3582,
16350,
23159,
1031,
12,
47,
13,
11116,
1930,
12417,
1930,
3261,
8666,
18,
4218,
2132,
2162,
13564,
2405,
5668,
16,
2154,
2278,
3951,
3696,
4407,
1930,
7018,
18,
10743,
26497,
29043,
18326,
1922,
2868,
16350,
23159,
2268,
15861,
2132,
2258,
2252,
28177,
2568,
16,
1930,
1920,
2856,
1977,
26687,
18,
2288,
16341,
17,
5778,
16350,
23159,
2268,
15861,
2132,
16687,
6190,
3291,
1927,
2310,
26497,
29043,
12871,
7018,
2894,
2311,
1988,
3261,
3582,
16350,
23159,
1031,
12,
47,
13,
11116,
18,
2038,
7149,
1988,
16350,
23159,
1031,
12,
47,
13,
11116,
7042,
27083,
16,
1920,
3044,
12905,
4113,
18,
1920,
2455,
1927,
27083,
5210,
2037,
22852,
2616,
7033,
2094,
12,
5890,
1031,
17,
21,
13,
1988,
1985,
5674,
1922,
1920,
2990,
1927,
19211,
1982,
3028,
1922,
3723,
1942,
1988,
5210,
2037,
2094,
5674,
2979,
19211,
18,
9541,
8767,
10680,
16350,
23159,
1031,
12,
47,
13,
11116,
17,
5069,
27083,
2455,
2469,
4057,
1942,
1920,
3733,
2024,
4996,
2019,
43,
4242,
1927,
21,
18,
2637,
2629,
1927,
9541,
8767,
2079,
21,
2629,
1927,
5268,
17,
19211,
18,
20403,
17,
27083,
2455,
1982,
5069,
2007,
8013,
5268,
17,
19211,
1942,
1920,
3381,
3227,
5515,
16,
1930,
1920,
2459,
1927,
9541,
8767,
1942,
1920,
3227,
5515,
8715,
2052,
3523,
18,
2303,
3620,
4300,
16,
54,
17,
9446,
2053,
1930,
4666,
2053,
2811,
2084,
4081,
27083,
2455,
18,
2342,
2230,
3220,
1988,
10743,
26497,
29043,
18326,
1922,
16350,
23159,
2268,
8754,
1977,
1920,
3211,
1927,
27083,
3523,
2007,
16350,
23159,
1031,
12,
47,
13,
11116,
1930,
1988,
1920,
12584,
2856,
1927,
2052,
3523,
1977,
1920,
2835,
1927,
16350,
23159,
1031,
12,
47,
13,
11116,
1956,
9541,
2019,
1920,
3500,
3200,
1927,
27083,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
16380905 | [
"Bipolar",
"I",
"disorder",
"and",
"schizophrenia:",
"a",
"440-single-nucleotide",
"polymorphism",
"screen",
"of",
"64",
"candidate",
"genes",
"among",
"Ashkenazi",
"Jewish",
"case-parent",
"trios.",
"Bipolar,",
"schizophrenia,",
"and",
"schizoaffective",
"disorders",
"are",
"common,",
"highly",
"heritable",
"psychiatric",
"disorders,",
"for",
"which",
"familial",
"coaggregation,",
"as",
"well",
"as",
"epidemiological",
"and",
"genetic",
"evidence,",
"suggests",
"overlapping",
"etiologies.",
"No",
"definitive",
"susceptibility",
"genes",
"have",
"yet",
"been",
"identified",
"for",
"any",
"of",
"these",
"disorders.",
"Genetic",
"heterogeneity,",
"combined",
"with",
"phenotypic",
"imprecision",
"and",
"poor",
"marker",
"coverage,",
"has",
"contributed",
"to",
"the",
"difficulty",
"in",
"defining",
"risk",
"variants.",
"We",
"focused",
"on",
"families",
"of",
"Ashkenazi",
"Jewish",
"descent,",
"to",
"reduce",
"genetic",
"heterogeneity,",
"and,",
"as",
"a",
"precursor",
"to",
"genomewide",
"association",
"studies,",
"we",
"undertook",
"a",
"single-nucleotide",
"polymorphism",
"(SNP)",
"genotyping",
"screen",
"of",
"64",
"candidate",
"genes",
"(440",
"SNPs)",
"chosen",
"on",
"the",
"basis",
"of",
"previous",
"linkage",
"or",
"of",
"association",
"and/or",
"biological",
"relevance.",
"We",
"genotyped",
"an",
"average",
"of",
"6.9",
"SNPs",
"per",
"gene,",
"with",
"an",
"average",
"density",
"of",
"1",
"SNP",
"per",
"11.9",
"kb",
"in",
"323",
"bipolar",
"I",
"disorder",
"and",
"274",
"schizophrenia",
"or",
"schizoaffective",
"Ashkenazi",
"case-parent",
"trios.",
"Using",
"single-SNP",
"and",
"haplotype-based",
"transmission/disequilibrium",
"tests,",
"we",
"ranked",
"genes",
"on",
"the",
"basis",
"of",
"strength",
"of",
"association",
"(P<.01).",
"Six",
"genes",
"(",
"DAO",
",",
"GRM3",
",",
"GRM4",
",",
"GRIN2B",
",",
"IL2RB",
",",
"and",
"TUBA8",
")",
"met",
"this",
"criterion",
"for",
"bipolar",
"I",
"disorder;",
"only",
"DAO",
" ",
"has",
"been",
"previously",
"associated",
"with",
"bipolar",
"disorder.",
"Six",
"genes",
"(",
"RGS4",
",",
"SCA1",
",",
"GRM4",
",",
"DPYSL2",
",",
"NOS1",
",",
"and",
"GRID1",
")",
"met",
"this",
"criterion",
"for",
"schizophrenia",
"or",
"schizoaffective",
"disorder;",
"five",
"replicate",
"previous",
"associations,",
"and",
"one,",
"GRID1",
",",
"shows",
"a",
"novel",
"association",
"with",
"schizophrenia.",
"In",
"addition,",
"six",
"genes",
"(",
"DPYSL2",
",",
"DTNBP1",
",",
"G30/G72",
",",
"GRID1",
",",
"GRM4",
",",
"and",
"NOS1",
")",
"showed",
"overlapping",
"suggestive",
"evidence",
"of",
"association",
"in",
"both",
"disorders.",
"These",
"results",
"may",
"help",
"to",
"prioritize",
"candidate",
"genes",
"for",
"future",
"study",
"from",
"among",
"the",
"many",
"suspected/proposed",
"for",
"schizophrenia",
"and",
"bipolar",
"disorders.",
"They",
"provide",
"further",
"support",
"for",
"shared",
"genetic",
"susceptibility",
"between",
"these",
"two",
"disorders",
"that",
"involve",
"glutamate-signaling",
"pathways."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
1,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
1,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
1,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes ( DAO , GRM3 , GRM4 , GRIN2B , IL2RB , and TUBA8 ) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes ( RGS4 , SCA1 , GRM4 , DPYSL2 , NOS1 , and GRID1 ) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1 , shows a novel association with schizophrenia. In addition, six genes ( DPYSL2 , DTNBP1 , G30/G72 , GRID1 , GRM4 , and NOS1 ) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways. | [
2,
10275,
51,
4770,
1930,
7899,
30,
43,
22042,
17,
2957,
17,
5489,
8218,
7053,
1927,
4723,
6610,
2628,
2706,
13696,
11341,
3408,
1033,
28296,
2471,
3087,
17,
6162,
30224,
1036,
18,
10275,
16,
7899,
16,
1930,
7071,
6952,
11978,
12323,
4414,
2032,
3059,
16,
3626,
22851,
7652,
4414,
16,
1958,
2154,
11444,
10027,
3312,
3127,
1943,
16,
1966,
2486,
1966,
9591,
1930,
3299,
3095,
16,
4015,
8984,
22608,
18,
2239,
12072,
6461,
2628,
2162,
4898,
2252,
2899,
1958,
2967,
1927,
2144,
4414,
18,
3299,
6808,
16,
4252,
1956,
8189,
26385,
3398,
1930,
3930,
4966,
6745,
16,
2258,
6505,
1942,
1920,
8791,
1922,
11266,
2565,
4936,
18,
2038,
5625,
1990,
5767,
1927,
13696,
11341,
3408,
1033,
28296,
2471,
19729,
16,
1942,
4412,
3299,
6808,
16,
1930,
16,
1966,
43,
7897,
1942,
3843,
7641,
3279,
2351,
16,
2038,
23111,
43,
2957,
17,
5489,
8218,
12,
6821,
13,
10667,
7053,
1927,
4723,
6610,
2628,
12,
22042,
6084,
13,
6724,
1990,
1920,
4859,
1927,
2555,
8611,
2014,
1927,
3279,
1930,
19,
2014,
3933,
8043,
18,
2038,
14401,
1925,
3361,
1927,
26,
18,
29,
6084,
2079,
2359,
16,
1956,
1925,
3361,
3824,
1927,
21,
6821,
2079,
2513,
18,
29,
6633,
1922,
24792,
10275,
51,
4770,
1930,
23092,
7899,
2014,
7071,
6952,
11978,
12323,
13696,
11341,
3408,
1033,
3087,
17,
6162,
30224,
1036,
18,
2193,
2957,
17,
6821,
1930,
10949,
17,
2454,
5303,
19,
19264,
4026,
16,
2038,
13188,
2628,
1990,
1920,
4859,
1927,
4568,
1927,
3279,
12,
58,
32,
18,
3287,
13,
18,
3798,
2628,
12,
3692,
1037,
16,
2398,
17796,
16,
2398,
1035,
1006,
16,
2398,
24444,
1014,
16,
28846,
16007,
16,
1930,
3710,
1019,
1025,
13,
2130,
2052,
8903,
1958,
10275,
51,
4770,
31,
2444,
3692,
1037,
2258,
2252,
3024,
2458,
1956,
10275,
4770,
18,
3798,
2628,
12,
18119,
1006,
16,
17529,
1009,
16,
2398,
1035,
1006,
16,
5679,
2012,
11232,
16,
9291,
1009,
16,
1930,
10765,
1009,
13,
2130,
2052,
8903,
1958,
7899,
2014,
7071,
6952,
11978,
12323,
4770,
31,
3628,
10525,
2555,
5253,
16,
1930,
2340,
16,
10765,
1009,
16,
3661,
43,
4008,
3279,
1956,
7899,
18,
1922,
2459,
16,
3798,
2628,
12,
5679,
2012,
11232,
16,
7711,
17046,
5113,
16,
15991,
1008,
19,
49,
10180,
16,
10765,
1009,
16,
2398,
1035,
1006,
16,
1930,
9291,
1009,
13,
2594,
8984,
12855,
3095,
1927,
3279,
1922,
2321,
4414,
18,
2144,
2274,
2278,
4087,
1942,
29179,
6610,
2628,
1958,
4115,
2161,
2037,
2706,
1920,
3086,
9407,
19,
4211,
1958,
7899,
1930,
10275,
4414,
18,
2611,
3394,
2520,
3373,
1958,
7115,
3299,
6461,
2192,
2144,
2288,
4414,
1988,
8156,
7627,
17,
3197,
3873,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
0,
1,
2,
2,
0,
1,
2,
2,
0,
1,
2,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
0,
1,
2,
2,
0,
1,
2,
2,
0,
1,
2,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
1,
2,
2,
0,
1,
2,
2,
2,
2,
0,
1,
2,
0,
1,
2,
2,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
7485151 | [
"Mutations",
"in",
"SOX9",
",",
"the",
"gene",
"responsible",
"for",
"Campomelic",
"dysplasia",
"and",
"autosomal",
"sex",
"reversal.",
"Campomelic",
"dysplasia",
"(CD)",
"is",
"a",
"skeletal",
"malformation",
"syndrome",
"frequently",
"accompanied",
"by",
"46,XY",
"sex",
"reversal.",
"A",
"mutation-screening",
"strategy",
"using",
"SSCP",
"was",
"employed",
"to",
"identify",
"mutations",
"in",
"SOX9",
",",
"the",
"chromosome",
"17q24",
"gene",
"responsible",
"for",
"CD",
"and",
"autosomal",
"sex",
"reversal",
"in",
"man.",
"We",
"have",
"screened",
"seven",
"CD",
"patients",
"with",
"no",
"cytologically",
"detectable",
"chromosomal",
"aberrations",
"and",
"two",
"CD",
"patients",
"with",
"chromosome",
"17",
"rearrangements",
"for",
"mutations",
"in",
"the",
"entire",
"open",
"reading",
"frame",
"of",
"SOX9",
".",
"Five",
"different",
"mutations",
"have",
"been",
"identified",
"in",
"six",
"CD",
"patients:",
"two",
"missense",
"mutations",
"in",
"the",
"SOX9",
" ",
"putative",
"DNA",
"binding",
"domain",
"(high",
"mobility",
"group,",
"or",
"HMG,",
"box);",
"three",
"frameshift",
"mutations",
"and",
"a",
"splice-acceptor",
"mutation.",
"An",
"identical",
"frameshift",
"mutation",
"is",
"found",
"in",
"two",
"unrelated",
"46,XY",
"patients,",
"one",
"exhibiting",
"a",
"male",
"phenotype",
"and",
"the",
"other",
"displaying",
"a",
"female",
"phenotype",
"(XY",
"sex",
"reversal).",
"All",
"mutations",
"found",
"affect",
"a",
"single",
"allele,",
"which",
"is",
"consistent",
"with",
"a",
"dominant",
"mode",
"of",
"inheritance.",
"No",
"mutations",
"were",
"found",
"in",
"the",
"SOX9",
" ",
"open",
"reading",
"frame",
"of",
"two",
"patients",
"with",
"chromosome",
"17q",
"rearrangements,",
"suggesting",
"that",
"the",
"translocations",
"affect",
"SOX9",
" ",
"expression.",
"These",
"findings",
"are",
"consistent",
"with",
"the",
"hypothesis",
"that",
"CD",
"results",
"from",
"haploinsufficiency",
"of",
"SOX9",
"."
] | [
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0
] | Mutations in SOX9 , the gene responsible for Campomelic dysplasia and autosomal sex reversal. Campomelic dysplasia (CD) is a skeletal malformation syndrome frequently accompanied by 46,XY sex reversal. A mutation-screening strategy using SSCP was employed to identify mutations in SOX9 , the chromosome 17q24 gene responsible for CD and autosomal sex reversal in man. We have screened seven CD patients with no cytologically detectable chromosomal aberrations and two CD patients with chromosome 17 rearrangements for mutations in the entire open reading frame of SOX9 . Five different mutations have been identified in six CD patients: two missense mutations in the SOX9 putative DNA binding domain (high mobility group, or HMG, box); three frameshift mutations and a splice-acceptor mutation. An identical frameshift mutation is found in two unrelated 46,XY patients, one exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). All mutations found affect a single allele, which is consistent with a dominant mode of inheritance. No mutations were found in the SOX9 open reading frame of two patients with chromosome 17q rearrangements, suggesting that the translocations affect SOX9 expression. These findings are consistent with the hypothesis that CD results from haploinsufficiency of SOX9 . | [
2,
3527,
1922,
19817,
16,
1920,
2359,
5061,
1958,
6225,
2225,
3742,
14095,
1930,
13027,
3486,
12393,
18,
6225,
2225,
3742,
14095,
12,
2464,
13,
1977,
43,
7345,
22138,
4741,
5467,
7936,
2007,
4182,
16,
20593,
3486,
12393,
18,
43,
3979,
17,
4449,
4884,
2193,
13061,
1034,
1982,
5789,
1942,
3512,
3527,
1922,
19817,
16,
1920,
5597,
2752,
23470,
1006,
2359,
5061,
1958,
2464,
1930,
13027,
3486,
12393,
1922,
2323,
18,
2038,
2162,
8582,
5260,
2464,
2132,
1956,
2239,
22004,
1954,
7398,
9220,
16303,
1930,
2288,
2464,
2132,
1956,
5597,
2752,
13955,
1958,
3527,
1922,
1920,
5346,
4437,
7461,
7673,
1927,
19817,
18,
3628,
2413,
3527,
2162,
2252,
2899,
1922,
3798,
2464,
2132,
30,
2288,
13519,
3527,
1922,
1920,
19817,
6770,
2678,
2743,
3418,
12,
2149,
8471,
2210,
16,
2014,
12058,
16,
5758,
13,
31,
2559,
21848,
3527,
1930,
43,
10708,
17,
12641,
3979,
18,
1925,
6119,
21848,
3979,
1977,
2435,
1922,
2288,
10295,
4182,
16,
20593,
2132,
16,
2340,
12196,
43,
4005,
4629,
1930,
1920,
2303,
13867,
43,
4232,
4629,
12,
20593,
3486,
12393,
13,
18,
2136,
3527,
2435,
4081,
43,
2957,
5465,
16,
2154,
1977,
3499,
1956,
43,
6379,
5754,
1927,
15762,
18,
2239,
3527,
1985,
2435,
1922,
1920,
19817,
4437,
7461,
7673,
1927,
2288,
2132,
1956,
5597,
2752,
1055,
13955,
16,
3783,
1988,
1920,
22436,
4081,
19817,
2294,
18,
2144,
3056,
2032,
3499,
1956,
1920,
4676,
1988,
2464,
2274,
2037,
27758,
12219,
1927,
19817,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
-100
] |
11139239 | [
"Jagged1",
"mutations",
"in",
"alagille",
"syndrome.",
"We",
"have",
"summarized",
"data",
"on",
"233",
"Alagille",
"syndrome",
"patients",
"reported",
"with",
"mutations",
"in",
"Jagged1",
" ",
"(",
"JAG1",
"Jagged1",
" ",
"mutations",
"in",
"alagille",
"syndrome.",
"We",
"have",
"summarized",
"data",
"on",
"233",
"Alagille",
"syndrome",
"patients",
"reported",
"with",
"mutations",
"in",
"Jagged1",
"(JAG1).",
"This",
"data",
"has",
"been",
"published",
"by",
"seven",
"different",
"laboratories",
"in",
"Europe,",
"the",
"United",
"States,",
"Australia,",
"and",
"Japan.",
"Mutations",
"have",
"been",
"demonstrated",
"in",
"60-75%",
"of",
"patients",
"with",
"a",
"clinically",
"confirmed",
"diagnosis",
"of",
"Alagille",
"syndrome.",
"Total",
"gene",
"deletions",
"have",
"been",
"reported",
"in",
"3-7%",
"of",
"patients,",
"and",
"the",
"remainder",
"have",
"intragenic",
"mutations.",
"Seventy",
"two",
"percent",
"(168/233)",
"of",
"the",
"reported",
"mutations",
"lead",
"to",
"frameshifts",
"that",
"cause",
"a",
"premature",
"termination",
"codon.",
"These",
"mutations",
"will",
"either",
"lead",
"to",
"a",
"prematurely",
"truncated",
"protein,",
"or",
"alternatively,",
"nonsense",
"mediated",
"decay",
"might",
"lead",
"to",
"lack",
"of",
"a",
"product",
"from",
"that",
"allele.",
"Twenty",
"three",
"unique",
"missense",
"mutations",
"were",
"identified",
"(13%",
"of",
"mutations).",
"These",
"were",
"clustered",
"in",
"conserved",
"regions",
"at",
"the",
"5'",
"end",
"of",
"the",
"gene,",
"or",
"in",
"the",
"EGF",
"repeats.",
"Splicing",
"consensus",
"sequence",
"changes",
"were",
"identified",
"in",
"15%",
"of",
"patients.",
"A",
"high",
"frequency",
"of",
"de",
"novo",
"mutations",
"(60-70%)",
"has",
"been",
"reported.",
"The",
"spectrum",
"of",
"mutations",
"identified",
"is",
"consistent",
"with",
"haploinsufficiency",
"for",
"JAG1",
" ",
"being",
"a",
"mechanism",
"for",
"Alagille",
"syndrome."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0
] | Jagged1 mutations in alagille syndrome. We have summarized data on 233 Alagille syndrome patients reported with mutations in Jagged1 ( JAG1 Jagged1 mutations in alagille syndrome. We have summarized data on 233 Alagille syndrome patients reported with mutations in Jagged1 (JAG1). This data has been published by seven different laboratories in Europe, the United States, Australia, and Japan. Mutations have been demonstrated in 60-75% of patients with a clinically confirmed diagnosis of Alagille syndrome. Total gene deletions have been reported in 3-7% of patients, and the remainder have intragenic mutations. Seventy two percent (168/233) of the reported mutations lead to frameshifts that cause a premature termination codon. These mutations will either lead to a prematurely truncated protein, or alternatively, nonsense mediated decay might lead to lack of a product from that allele. Twenty three unique missense mutations were identified (13% of mutations). These were clustered in conserved regions at the 5' end of the gene, or in the EGF repeats. Splicing consensus sequence changes were identified in 15% of patients. A high frequency of de novo mutations (60-70%) has been reported. The spectrum of mutations identified is consistent with haploinsufficiency for JAG1 being a mechanism for Alagille syndrome. | [
2,
21153,
4428,
1009,
3527,
1922,
10527,
6121,
11560,
1021,
4741,
18,
2038,
2162,
8440,
2230,
1990,
19598,
10527,
6121,
11560,
1021,
4741,
2132,
2568,
1956,
3527,
1922,
21153,
4428,
1009,
12,
21153,
1009,
21153,
4428,
1009,
3527,
1922,
10527,
6121,
11560,
1021,
4741,
18,
2038,
2162,
8440,
2230,
1990,
19598,
10527,
6121,
11560,
1021,
4741,
2132,
2568,
1956,
3527,
1922,
21153,
4428,
1009,
12,
21153,
1009,
13,
18,
2052,
2230,
2258,
2252,
4586,
2007,
5260,
2413,
7710,
1922,
5560,
16,
1920,
6128,
4376,
16,
10014,
16,
1930,
5834,
18,
3527,
2162,
2252,
3161,
1922,
3276,
17,
4089,
9,
1927,
2132,
1956,
43,
5908,
3982,
3574,
1927,
10527,
6121,
11560,
1021,
4741,
18,
2698,
2359,
10550,
2162,
2252,
2568,
1922,
23,
17,
27,
9,
1927,
2132,
16,
1930,
1920,
15834,
2162,
27911,
7245,
3527,
18,
16270,
2288,
3564,
12,
14004,
19,
19598,
13,
1927,
1920,
2568,
3527,
2949,
1942,
21848,
1036,
1988,
3936,
43,
9839,
12462,
8905,
18,
2144,
3527,
2832,
3108,
2949,
1942,
43,
28283,
9530,
2213,
16,
2014,
9242,
16,
19605,
3434,
9310,
3284,
2949,
1942,
3630,
1927,
43,
4863,
2037,
1988,
5465,
18,
7639,
2559,
5008,
13519,
3527,
1985,
2899,
12,
2590,
9,
1927,
3527,
13,
18,
2144,
1985,
11049,
1922,
5305,
3451,
2019,
1920,
25,
11,
2482,
1927,
1920,
2359,
16,
2014,
1922,
1920,
4451,
9569,
18,
8490,
7076,
3244,
2840,
1985,
2899,
1922,
2461,
9,
1927,
2132,
18,
43,
2149,
3528,
1927,
2028,
9441,
3527,
12,
3276,
17,
3895,
9,
13,
2258,
2252,
2568,
18,
1920,
5648,
1927,
3527,
2899,
1977,
3499,
1956,
27758,
12219,
1958,
21153,
1009,
3301,
43,
2856,
1958,
10527,
6121,
11560,
1021,
4741,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
1,
2,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
18683858 | [
"Ancestry",
"informative",
"marker",
"sets",
"for",
"determining",
"continental",
"origin",
"and",
"admixture",
"proportions",
"in",
"common",
"populations",
"in",
"America.",
"To",
"provide",
"a",
"resource",
"for",
"assessing",
"continental",
"ancestry",
"in",
"a",
"wide",
"variety",
"of",
"genetic",
"studies,",
"we",
"identified,",
"validated,",
"and",
"characterized",
"a",
"set",
"of",
"128",
"ancestry",
"informative",
"markers",
"(AIMs).",
"The",
"markers",
"were",
"chosen",
"for",
"informativeness,",
"genome-wide",
"distribution,",
"and",
"genotype",
"reproducibility",
"on",
"two",
"platforms",
"(TaqMan",
"assays",
"and",
"Illumina",
"arrays).",
"We",
"analyzed",
"genotyping",
"data",
"from",
"825",
"subjects",
"with",
"diverse",
"ancestry,",
"including",
"European,",
"East",
"Asian,",
"Amerindian,",
"African,",
"South",
"Asian,",
"Mexican,",
"and",
"Puerto",
"Rican.",
"A",
"comprehensive",
"set",
"of",
"128",
"AIMs",
"and",
"subsets",
"as",
"small",
"as",
"24",
"AIMs",
"are",
"shown",
"to",
"be",
"useful",
"tools",
"for",
"ascertaining",
"the",
"origin",
"of",
"subjects",
"from",
"particular",
"continents,",
"and",
"to",
"correct",
"for",
"population",
"stratification",
"in",
"admixed",
"population",
"sample",
"sets.",
"Our",
"findings",
"provide",
"general",
"guidelines",
"for",
"the",
"application",
"of",
"specific",
"AIM",
"subsets",
"as",
"a",
"resource",
"for",
"wide",
"application.",
"We",
"conclude",
"that",
"investigators",
"can",
"use",
"TaqMan",
"assays",
"for",
"the",
"selected",
"AIMs",
"as",
"a",
"simple",
"and",
"cost",
"efficient",
"tool",
"to",
"control",
"for",
"differences",
"in",
"continental",
"ancestry",
"when",
"conducting",
"association",
"studies",
"in",
"ethnically",
"diverse",
"populations."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. To provide a resource for assessing continental ancestry in a wide variety of genetic studies, we identified, validated, and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations. | [
2,
15419,
12840,
4966,
5704,
1958,
7426,
26540,
4853,
1930,
22941,
9766,
1922,
3059,
4098,
1922,
10390,
18,
1942,
3394,
43,
7965,
1958,
7665,
26540,
15419,
1922,
43,
4743,
5386,
1927,
3299,
2351,
16,
2038,
2899,
16,
6593,
16,
1930,
4378,
43,
2735,
1927,
9100,
15419,
12840,
4432,
12,
8267,
13,
18,
1920,
4432,
1985,
6724,
1958,
12840,
2971,
16,
3843,
17,
4743,
3282,
16,
1930,
5619,
11998,
1990,
2288,
13334,
12,
15161,
4614,
1930,
10379,
10517,
13,
18,
2038,
3265,
10667,
2230,
2037,
6175,
1015,
3297,
1956,
6445,
15419,
16,
2710,
6785,
16,
10319,
9686,
16,
2150,
16654,
7408,
1928,
16,
7050,
16,
6061,
9686,
16,
17165,
16,
1930,
25425,
18091,
1928,
18,
43,
6911,
2735,
1927,
9100,
8267,
1930,
9524,
1966,
2858,
1966,
2686,
8267,
2032,
2522,
1942,
1998,
4707,
6257,
1958,
13883,
1941,
1920,
4853,
1927,
3297,
2037,
3278,
26789,
1036,
16,
1930,
1942,
5550,
1958,
2973,
12881,
1922,
21694,
1919,
2973,
2983,
5704,
18,
2342,
3056,
3394,
3335,
5522,
1958,
1920,
4722,
1927,
2487,
3774,
9524,
1966,
43,
7965,
1958,
4743,
4722,
18,
2038,
7676,
1988,
9427,
2112,
2485,
15161,
4614,
1958,
1920,
3790,
8267,
1966,
43,
5288,
1930,
4455,
5807,
5229,
1942,
2285,
1958,
2886,
1922,
26540,
15419,
2469,
12335,
3279,
2351,
1922,
8639,
2169,
6445,
4098,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1415228 | [
"The",
"tyrosinase-positive",
"oculocutaneous",
"albinism",
"locus",
"maps",
"to",
"chromosome",
"15q11.2-q12.",
"Tyrosinase-positive",
"oculocutaneous",
"albinism",
"(ty-pos",
"OCA),",
"an",
"autosomal",
"recessive",
"disorder",
"of",
"the",
"melanin",
"biosynthetic",
"pathway,",
"is",
"the",
"most",
"common",
"type",
"of",
"albinism",
"occurring",
"worldwide.",
"In",
"southern",
"African",
"Bantu-speaking",
"negroids",
"it",
"has",
"an",
"overall",
"prevalence",
"of",
"about",
"1/3,900.",
"Since",
"the",
"basic",
"biochemical",
"defect",
"is",
"unknown,",
"a",
"linkage",
"study",
"with",
"candidate",
"loci,",
"candidate",
"chromosomal",
"regions,",
"and",
"random",
"loci",
"was",
"undertaken.",
"The",
"ty-pos",
"OCA",
"locus",
"was",
"found",
"to",
"be",
"linked",
"to",
"two",
"arbitrary",
"loci,",
"D15S10",
"and",
"D15S13,",
"in",
"the",
"Prader-Willi/Angelman",
"chromosomal",
"region",
"on",
"chromosome",
"15q11.2-q12.",
"The",
"pink-eyed",
"dilute",
"locus,",
"p,",
"on",
"mouse",
"chromosome",
"7,",
"maps",
"close",
"to",
"a",
"region",
"of",
"homology",
"on",
"human",
"chromosome",
"15q,",
"and",
"we",
"postulate",
"that",
"the",
"ty-pos",
"OCA",
"and",
"p",
"loci",
"are",
"homologous."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12. Tyrosinase-positive oculocutaneous albinism (ty-pos OCA), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common type of albinism occurring worldwide. In southern African Bantu-speaking negroids it has an overall prevalence of about 1/3,900. Since the basic biochemical defect is unknown, a linkage study with candidate loci, candidate chromosomal regions, and random loci was undertaken. The ty-pos OCA locus was found to be linked to two arbitrary loci, D15S10 and D15S13, in the Prader-Willi/Angelman chromosomal region on chromosome 15q11.2-q12. The pink-eyed dilute locus, p, on mouse chromosome 7, maps close to a region of homology on human chromosome 15q, and we postulate that the ty-pos OCA and p loci are homologous. | [
2,
1920,
27083,
17,
2843,
25669,
29011,
5311,
15472,
1035,
6730,
7422,
1942,
5597,
2461,
23931,
18,
22,
17,
22027,
1028,
18,
27083,
17,
2843,
25669,
29011,
5311,
15472,
1035,
12,
6227,
17,
2159,
5084,
1019,
13,
16,
1925,
13027,
13992,
4770,
1927,
1920,
20850,
14041,
3374,
16,
1977,
1920,
2501,
3059,
2601,
1927,
5311,
15472,
1035,
6966,
8563,
18,
1922,
9257,
7050,
15114,
1031,
1032,
17,
15073,
2922,
12245,
1036,
2176,
2258,
1925,
3399,
4077,
1927,
3001,
21,
19,
23,
16,
13886,
18,
3328,
1920,
5937,
6503,
7374,
1977,
5435,
16,
43,
8611,
2161,
1956,
6610,
6971,
16,
6610,
9220,
3451,
16,
1930,
3332,
6971,
1982,
10466,
18,
1920,
6227,
17,
2159,
5084,
1019,
6730,
1982,
2435,
1942,
1998,
4624,
1942,
2288,
14346,
6971,
16,
8524,
1015,
12030,
1008,
1930,
8524,
1015,
12030,
1010,
16,
1922,
1920,
21227,
2179,
17,
13909,
19,
29021,
3862,
9220,
3031,
1990,
5597,
2461,
23931,
18,
22,
17,
22027,
1028,
18,
1920,
13375,
17,
5723,
1007,
24268,
6730,
16,
58,
16,
1990,
3321,
5597,
27,
16,
7422,
5428,
1942,
43,
3031,
1927,
9039,
1990,
2616,
5597,
2461,
1055,
16,
1930,
2038,
23911,
1988,
1920,
6227,
17,
2159,
5084,
1019,
1930,
58,
6971,
2032,
8725,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
21786366 | [
"Exome",
"sequencing",
"identifies",
"MRPL3",
" ",
"mutation",
"in",
"mitochondrial",
"cardiomyopathy.",
"By",
"combining",
"exome",
"sequencing",
"in",
"conjunction",
"with",
"genetic",
"mapping,",
"we",
"have",
"identified",
"the",
"first",
"mutation",
"in",
"large",
"mitochondrial",
"ribosomal",
"protein",
"MRPL3",
" ",
"in",
"a",
"family",
"of",
"four",
"sibs",
"with",
"hypertrophic",
"cardiomyopathy,",
"psychomotor",
"retardation,",
"and",
"multiple",
"respiratory",
"chain",
"deficiency.",
"Affected",
"sibs",
"were",
"compound",
"heterozygotes",
"for",
"a",
"missense",
"MRPL3",
"mutation",
"(",
"P317R",
"MRPL3",
" ",
"mutation",
"(P317R)",
"and",
"a",
"large-scale",
"deletion,",
"inherited",
"from",
"the",
"mother",
"and",
"the",
"father,",
"respectively.",
"These",
"mutations",
"were",
"shown",
"to",
"alter",
"ribosome",
"assembly",
"and",
"cause",
"a",
"mitochondrial",
"translation",
"deficiency",
"in",
"cultured",
"skin",
"fibroblasts",
"resulting",
"in",
"an",
"abnormal",
"assembly",
"of",
"several",
"complexes",
"of",
"the",
"respiratory",
"chain.",
"This",
"observation",
"gives",
"support",
"to",
"the",
"view",
"that",
"exome",
"sequencing",
"combined",
"with",
"genetic",
"mapping",
"is",
"a",
"powerful",
"approach",
"for",
"the",
"identification",
"of",
"new",
"genes",
"of",
"mitochondrial",
"disorders."
] | [
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy. By combining exome sequencing in conjunction with genetic mapping, we have identified the first mutation in large mitochondrial ribosomal protein MRPL3 in a family of four sibs with hypertrophic cardiomyopathy, psychomotor retardation, and multiple respiratory chain deficiency. Affected sibs were compound heterozygotes for a missense MRPL3 mutation ( P317R MRPL3 mutation (P317R) and a large-scale deletion, inherited from the mother and the father, respectively. These mutations were shown to alter ribosome assembly and cause a mitochondrial translation deficiency in cultured skin fibroblasts resulting in an abnormal assembly of several complexes of the respiratory chain. This observation gives support to the view that exome sequencing combined with genetic mapping is a powerful approach for the identification of new genes of mitochondrial disorders. | [
2,
16390,
4754,
14133,
27997,
15303,
3979,
1922,
4596,
14141,
18,
2007,
9138,
16390,
4754,
1922,
11799,
1956,
3299,
7084,
16,
2038,
2162,
2899,
1920,
2561,
3979,
1922,
3103,
4596,
11196,
2213,
27997,
15303,
1922,
43,
3416,
1927,
3006,
9643,
1036,
1956,
17437,
14141,
16,
26261,
16342,
16,
1930,
3137,
5481,
4659,
6179,
18,
4218,
9643,
1036,
1985,
3547,
22910,
1958,
43,
13519,
27997,
15303,
3979,
12,
9234,
3952,
1005,
27997,
15303,
3979,
12,
9234,
3952,
1005,
13,
1930,
43,
3103,
17,
3536,
5541,
16,
12911,
2037,
1920,
7999,
1930,
1920,
14854,
16,
2763,
18,
2144,
3527,
1985,
2522,
1942,
4238,
12794,
5957,
1930,
3936,
43,
4596,
6410,
6179,
1922,
4789,
4407,
7001,
3864,
1922,
1925,
4552,
5957,
1927,
2980,
5048,
1927,
1920,
5481,
4659,
18,
2052,
5275,
10006,
3373,
1942,
1920,
4263,
1988,
16390,
4754,
4252,
1956,
3299,
7084,
1977,
43,
9974,
2998,
1958,
1920,
4824,
1927,
2814,
2628,
1927,
4596,
4414,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8981970 | [
"Expression",
"of",
"DAZ",
",",
"an",
"azoospermia",
"factor",
"candidate,",
"in",
"human",
"spermatogonia."
] | [
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0
] | Expression of DAZ , an azoospermia factor candidate, in human spermatogonia. | [
2,
2294,
1927,
3692,
1011,
16,
1925,
27381,
21901,
2126,
2991,
6610,
16,
1922,
2616,
10896,
30175,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
21549336 | [
"Nonsense",
"mutations",
"in",
"SMPX",
",",
"encoding",
"a",
"protein",
"responsive",
"to",
"physical",
"force,",
"result",
"in",
"X-chromosomal",
"hearing",
"loss.",
"The",
"fact",
"that",
"hereditary",
"hearing",
"loss",
"is",
"the",
"most",
"common",
"sensory",
"disorder",
"in",
"humans",
"is",
"reflected",
"by,",
"among",
"other",
"things,",
"an",
"extraordinary",
"allelic",
"and",
"nonallelic",
"genetic",
"heterogeneity.",
"X-chromosomal",
"hearing",
"impairment",
"represents",
"only",
"a",
"minor",
"fraction",
"of",
"all",
"cases.",
"In",
"a",
"study",
"of",
"a",
"Spanish",
"family",
"the",
"locus",
"for",
"one",
"of",
"the",
"X-chromosomal",
"forms",
"was",
"assigned",
"to",
"Xp22",
"(",
"DFNX4",
").",
"We",
"mapped",
"the",
"disease",
"locus",
"in",
"the",
"same",
"chromosomal",
"region",
"in",
"a",
"large",
"German",
"pedigree",
"with",
"X-chromosomal",
"nonsyndromic",
"hearing",
"impairment",
"by",
"using",
"genome-wide",
"linkage",
"analysis.",
"Males",
"presented",
"with",
"postlingual",
"hearing",
"loss",
"and",
"onset",
"at",
"ages",
"3-7,",
"whereas",
"onset",
"in",
"female",
"carriers",
"was",
"in",
"the",
"second",
"to",
"third",
"decades.",
"Targeted",
"DNA",
"capture",
"with",
"high-throughput",
"sequencing",
"detected",
"a",
"nonsense",
"mutation",
"in",
"the",
"small",
"muscle",
"protein,",
"X-linked",
"(",
"SMPX",
")",
"of",
"affected",
"individuals.",
"We",
"identified",
"another",
"nonsense",
"mutation",
"in",
"SMPX",
" ",
"in",
"patients",
"from",
"the",
"Spanish",
"family",
"who",
"were",
"previously",
"analyzed",
"to",
"map",
"DFNX4",
".",
"SMPX",
" ",
"encodes",
"an",
"88",
"amino",
"acid,",
"cytoskeleton-associated",
"protein",
"that",
"is",
"responsive",
"to",
"mechanical",
"stress.",
"The",
"presence",
"of",
"Smpx",
"in",
"hair",
"cells",
"and",
"supporting",
"cells",
"of",
"the",
"murine",
"cochlea",
"indicates",
"its",
"role",
"in",
"the",
"inner",
"ear.",
"The",
"nonsense",
"mutations",
"detected",
"in",
"the",
"two",
"families",
"suggest",
"a",
"loss-of-function",
"mechanism",
"underlying",
"this",
"form",
"of",
"hearing",
"impairment.",
"Results",
"obtained",
"after",
"heterologous",
"overexpression",
"of",
"SMPX",
"Smpx",
" ",
"in",
"hair",
"cells",
"and",
"supporting",
"cells",
"of",
"the",
"murine",
"cochlea",
"indicates",
"its",
"role",
"in",
"the",
"inner",
"ear.",
"The",
"nonsense",
"mutations",
"detected",
"in",
"the",
"two",
"families",
"suggest",
"a",
"loss-of-function",
"mechanism",
"underlying",
"this",
"form",
"of",
"hearing",
"impairment.",
"Results",
"obtained",
"after",
"heterologous",
"overexpression",
"of",
"SMPX",
"proteins",
"were",
"compatible",
"with",
"this",
"assumption.",
"Because",
"responsivity",
"to",
"physical",
"force",
"is",
"a",
"characteristic",
"feature",
"of",
"the",
"protein,",
"we",
"propose",
"that",
"long-term",
"maintenance",
"of",
"mechanically",
"stressed",
"inner-ear",
"cells",
"critically",
"depends",
"on",
"SMPX",
" ",
"function."
] | [
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0
] | Nonsense mutations in SMPX , encoding a protein responsive to physical force, result in X-chromosomal hearing loss. The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 ( DFNX4 ). We mapped the disease locus in the same chromosomal region in a large German pedigree with X-chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3-7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked ( SMPX ) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4 . SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner-ear cells critically depends on SMPX function. | [
2,
19605,
3527,
1922,
2426,
1034,
1039,
16,
5797,
43,
2213,
8487,
1942,
3841,
5495,
16,
3211,
1922,
66,
17,
9220,
8512,
3257,
18,
1920,
2371,
1988,
16321,
8512,
3257,
1977,
1920,
2501,
3059,
6893,
4770,
1922,
5209,
1977,
8830,
2007,
16,
2706,
2303,
15018,
16,
1925,
30424,
13045,
1930,
2447,
5915,
1935,
3299,
6808,
18,
66,
17,
9220,
8512,
6159,
4972,
2444,
43,
5857,
3906,
1927,
2136,
2919,
18,
1922,
43,
2161,
1927,
43,
13289,
3416,
1920,
6730,
1958,
2340,
1927,
1920,
66,
17,
9220,
4952,
1982,
6304,
1942,
15930,
4460,
12,
8122,
14272,
1006,
13,
18,
2038,
9225,
1920,
2573,
6730,
1922,
1920,
2841,
9220,
3031,
1922,
43,
3103,
12194,
22336,
1956,
66,
17,
9220,
23428,
3883,
3264,
8512,
6159,
2007,
2193,
3843,
17,
4743,
8611,
2333,
18,
5129,
3549,
1956,
2753,
3961,
2224,
8512,
3257,
1930,
4727,
2019,
7684,
23,
17,
27,
16,
3417,
4727,
1922,
4232,
8974,
1982,
1922,
1920,
2812,
1942,
4563,
8995,
18,
5154,
2678,
7573,
1956,
2149,
17,
9984,
4754,
3330,
43,
19605,
3979,
1922,
1920,
2858,
3760,
2213,
16,
66,
17,
4624,
12,
2426,
1034,
1039,
13,
1927,
4218,
3445,
18,
2038,
2899,
3741,
19605,
3979,
1922,
2426,
1034,
1039,
1922,
2132,
2037,
1920,
13289,
3416,
2746,
1985,
3024,
3265,
1942,
4446,
8122,
14272,
1006,
18,
2426,
1034,
1039,
9937,
1925,
5744,
3835,
2687,
16,
11612,
17,
2458,
2213,
1988,
1977,
8487,
1942,
5821,
3071,
18,
1920,
2990,
1927,
2426,
1034,
1039,
1922,
7018,
2094,
1930,
6184,
2094,
1927,
1920,
7135,
23310,
4538,
2496,
2770,
1922,
1920,
6671,
4352,
18,
1920,
19605,
3527,
3330,
1922,
1920,
2288,
5767,
3220,
43,
3257,
17,
1927,
17,
2347,
2856,
5030,
2052,
2386,
1927,
8512,
6159,
18,
2274,
2926,
2256,
15363,
5616,
1927,
2426,
1034,
1039,
2426,
1034,
1039,
1922,
7018,
2094,
1930,
6184,
2094,
1927,
1920,
7135,
23310,
4538,
2496,
2770,
1922,
1920,
6671,
4352,
18,
1920,
19605,
3527,
3330,
1922,
1920,
2288,
5767,
3220,
43,
3257,
17,
1927,
17,
2347,
2856,
5030,
2052,
2386,
1927,
8512,
6159,
18,
2274,
2926,
2256,
15363,
5616,
1927,
2426,
1034,
1039,
2697,
1985,
11290,
1956,
2052,
7235,
18,
2882,
2364,
10794,
1942,
3841,
5495,
1977,
43,
6293,
5961,
1927,
1920,
2213,
16,
2038,
8040,
1988,
2815,
17,
2576,
6291,
1927,
17841,
14438,
6671,
17,
4352,
2094,
9790,
7315,
1990,
2426,
1034,
1039,
2347,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
-100
] |
12489041 | [
"Distribution",
"patterns",
"of",
"postmortem",
"damage",
"in",
"human",
"mitochondrial",
"DNA.",
"The",
"distribution",
"of",
"postmortem",
"damage",
"in",
"mitochondrial",
"DNA",
"retrieved",
"from",
"37",
"ancient",
"human",
"DNA",
"samples",
"was",
"analyzed",
"by",
"cloning",
"and",
"was",
"compared",
"with",
"a",
"selection",
"of",
"published",
"animal",
"data.",
"A",
"relative",
"rate",
"of",
"damage",
"(rho(v))",
"was",
"calculated",
"for",
"nucleotide",
"positions",
"within",
"the",
"human",
"hypervariable",
"region",
"1",
"(HVR1)",
"and",
"cytochrome",
"oxidase",
"subunit",
"III",
"HVR1",
"human",
"hypervariable",
"region",
"1",
" ",
"(HVR1)",
"and",
"cytochrome",
"oxidase",
"subunit",
"III",
"genes.",
"A",
"comparison",
"of",
"damaged",
"sites",
"within",
"and",
"between",
"the",
"regions",
"reveals",
"that",
"damage",
"hotspots",
"exist",
"and",
"that,",
"in",
"the",
"HVR1",
",",
"these",
"correlate",
"with",
"sites",
"known",
"to",
"have",
"high",
"in",
"vivo",
"mutation",
"rates.",
"Conversely,",
"HVR1",
" ",
"subregions",
"with",
"known",
"structural",
"function,",
"such",
"as",
"MT5,",
"have",
"lower",
"in",
"vivo",
"mutation",
"rates",
"and",
"lower",
"postmortem-damage",
"rates.",
"The",
"postmortem",
"data",
"also",
"identify",
"a",
"possible",
"functional",
"subregion",
"of",
"the",
"HVR1",
",",
"termed",
"\"low-diversity",
"1,\"",
"through",
"the",
"lack",
"of",
"sequence",
"damage.",
"The",
"amount",
"of",
"postmortem",
"damage",
"observed",
"in",
"mitochondrial",
"coding",
"regions",
"was",
"significantly",
"lower",
"than",
"in",
"the",
"HVR1",
",",
"and,",
"although",
"hotspots",
"were",
"noted,",
"these",
"did",
"not",
"correlate",
"with",
"codon",
"position.",
"Finally,",
"a",
"simple",
"method",
"for",
"the",
"identification",
"of",
"incorrect",
"archaeological",
"haplogroup",
"designations",
"is",
"introduced,",
"on",
"the",
"basis",
"of",
"the",
"observed",
"spectrum",
"of",
"postmortem",
"damage."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
1,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Distribution patterns of postmortem damage in human mitochondrial DNA. The distribution of postmortem damage in mitochondrial DNA retrieved from 37 ancient human DNA samples was analyzed by cloning and was compared with a selection of published animal data. A relative rate of damage (rho(v)) was calculated for nucleotide positions within the human hypervariable region 1 (HVR1) and cytochrome oxidase subunit III HVR1 human hypervariable region 1 (HVR1) and cytochrome oxidase subunit III genes. A comparison of damaged sites within and between the regions reveals that damage hotspots exist and that, in the HVR1 , these correlate with sites known to have high in vivo mutation rates. Conversely, HVR1 subregions with known structural function, such as MT5, have lower in vivo mutation rates and lower postmortem-damage rates. The postmortem data also identify a possible functional subregion of the HVR1 , termed "low-diversity 1," through the lack of sequence damage. The amount of postmortem damage observed in mitochondrial coding regions was significantly lower than in the HVR1 , and, although hotspots were noted, these did not correlate with codon position. Finally, a simple method for the identification of incorrect archaeological haplogroup designations is introduced, on the basis of the observed spectrum of postmortem damage. | [
2,
3282,
4147,
1927,
19411,
4293,
1922,
2616,
4596,
2678,
18,
1920,
3282,
1927,
19411,
4293,
1922,
4596,
2678,
10931,
2037,
3191,
17364,
2616,
2678,
2785,
1982,
3265,
2007,
11501,
1930,
1982,
2452,
1956,
43,
4367,
1927,
4586,
4027,
2230,
18,
43,
3338,
2769,
1927,
4293,
12,
10585,
12,
64,
13,
13,
1982,
3561,
1958,
5489,
6490,
2651,
1920,
2616,
22028,
10104,
3031,
21,
12,
12948,
7011,
13,
1930,
9387,
10488,
5903,
4337,
12948,
7011,
2616,
22028,
10104,
3031,
21,
12,
12948,
7011,
13,
1930,
9387,
10488,
5903,
4337,
2628,
18,
43,
3723,
1927,
10756,
3402,
2651,
1930,
2192,
1920,
3451,
9179,
1988,
4293,
23429,
5516,
1930,
1988,
16,
1922,
1920,
12948,
7011,
16,
2144,
8474,
1956,
3402,
3171,
1942,
2162,
2149,
1922,
3597,
3979,
3389,
18,
8990,
16,
12948,
7011,
28605,
1956,
3171,
4346,
2347,
16,
2427,
1966,
4638,
1015,
16,
2162,
2826,
1922,
3597,
3979,
3389,
1930,
2826,
19411,
17,
4293,
3389,
18,
1920,
19411,
2230,
2222,
3512,
43,
3216,
3183,
22345,
2001,
1927,
1920,
12948,
7011,
16,
10266,
6,
2330,
17,
5935,
21,
16,
6,
2596,
1920,
3630,
1927,
3244,
4293,
18,
1920,
4351,
1927,
19411,
4293,
2528,
1922,
4596,
5804,
3451,
1982,
2567,
2826,
2254,
1922,
1920,
12948,
7011,
16,
1930,
16,
2876,
23429,
1985,
5040,
16,
2144,
2811,
2084,
8474,
1956,
8905,
3507,
18,
4342,
16,
43,
5288,
2417,
1958,
1920,
4824,
1927,
12984,
13470,
2477,
26953,
27806,
1036,
1977,
6373,
16,
1990,
1920,
4859,
1927,
1920,
2528,
5648,
1927,
19411,
4293,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
1,
2,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
12557124 | [
"Human",
"population",
"genetic",
"structure",
"and",
"inference",
"of",
"group",
"membership.",
"A",
"major",
"goal",
"of",
"biomedical",
"research",
"is",
"to",
"develop",
"the",
"capability",
"to",
"provide",
"highly",
"personalized",
"health",
"care.",
"To",
"do",
"so,",
"it",
"is",
"necessary",
"to",
"understand",
"the",
"distribution",
"of",
"interindividual",
"genetic",
"variation",
"at",
"loci",
"underlying",
"physical",
"characteristics,",
"disease",
"susceptibility,",
"and",
"response",
"to",
"treatment.",
"Variation",
"at",
"these",
"loci",
"commonly",
"exhibits",
"geographic",
"structuring",
"and",
"may",
"contribute",
"to",
"phenotypic",
"differences",
"between",
"groups.",
"Thus,",
"in",
"some",
"situations,",
"it",
"may",
"be",
"important",
"to",
"consider",
"these",
"groups",
"separately.",
"Membership",
"in",
"these",
"groups",
"is",
"commonly",
"inferred",
"by",
"use",
"of",
"a",
"proxy",
"such",
"as",
"place-of-origin",
"or",
"ethnic",
"affiliation.",
"These",
"inferences",
"are",
"frequently",
"weakened,",
"however,",
"by",
"use",
"of",
"surrogates,",
"such",
"as",
"skin",
"color,",
"for",
"these",
"proxies,",
"the",
"distribution",
"of",
"which",
"bears",
"little",
"resemblance",
"to",
"the",
"distribution",
"of",
"neutral",
"genetic",
"variation.",
"Consequently,",
"it",
"has",
"become",
"increasingly",
"controversial",
"whether",
"proxies",
"are",
"sufficient",
"and",
"accurate",
"representations",
"of",
"groups",
"inferred",
"from",
"neutral",
"genetic",
"variation.",
"This",
"raises",
"three",
"questions:",
"how",
"many",
"data",
"are",
"required",
"to",
"identify",
"population",
"structure",
"at",
"a",
"meaningful",
"level",
"of",
"resolution,",
"to",
"what",
"level",
"can",
"population",
"structure",
"be",
"resolved,",
"and",
"do",
"some",
"proxies",
"represent",
"population",
"structure",
"accurately?",
"We",
"assayed",
"100",
"Alu",
"insertion",
"polymorphisms",
"in",
"a",
"heterogeneous",
"collection",
"of",
"approximately",
"565",
"individuals,",
"approximately",
"200",
"of",
"whom",
"were",
"also",
"typed",
"for",
"60",
"microsatellites.",
"Stripped",
"of",
"identifying",
"information,",
"correct",
"assignment",
"to",
"the",
"continent",
"of",
"origin",
"(Africa,",
"Asia,",
"or",
"Europe)",
"with",
"a",
"mean",
"accuracy",
"of",
"at",
"least",
"90%",
"required",
"a",
"minimum",
"of",
"60",
"Alu",
"markers",
"or",
"microsatellites",
"and",
"reached",
"99%-100%",
"when",
">/=100",
"loci",
"were",
"used.",
"Less",
"accurate",
"assignment",
"(87%)",
"to",
"the",
"appropriate",
"genetic",
"cluster",
"was",
"possible",
"for",
"a",
"historically",
"admixed",
"sample",
"from",
"southern",
"India.",
"These",
"results",
"set",
"a",
"minimum",
"for",
"the",
"number",
"of",
"markers",
"that",
"must",
"be",
"tested",
"to",
"make",
"strong",
"inferences",
"about",
"detecting",
"population",
"structure",
"among",
"Old",
"World",
"populations",
"under",
"ideal",
"experimental",
"conditions.",
"We",
"note",
"that,",
"whereas",
"some",
"proxies",
"correspond",
"crudely,",
"if",
"at",
"all,",
"to",
"population",
"structure,",
"the",
"heuristic",
"value",
"of",
"others",
"is",
"much",
"higher.",
"This",
"suggests",
"that",
"a",
"more",
"flexible",
"framework",
"is",
"needed",
"for",
"making",
"inferences",
"about",
"population",
"structure",
"and",
"the",
"utility",
"of",
"proxies."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Human population genetic structure and inference of group membership. A major goal of biomedical research is to develop the capability to provide highly personalized health care. To do so, it is necessary to understand the distribution of interindividual genetic variation at loci underlying physical characteristics, disease susceptibility, and response to treatment. Variation at these loci commonly exhibits geographic structuring and may contribute to phenotypic differences between groups. Thus, in some situations, it may be important to consider these groups separately. Membership in these groups is commonly inferred by use of a proxy such as place-of-origin or ethnic affiliation. These inferences are frequently weakened, however, by use of surrogates, such as skin color, for these proxies, the distribution of which bears little resemblance to the distribution of neutral genetic variation. Consequently, it has become increasingly controversial whether proxies are sufficient and accurate representations of groups inferred from neutral genetic variation. This raises three questions: how many data are required to identify population structure at a meaningful level of resolution, to what level can population structure be resolved, and do some proxies represent population structure accurately? We assayed 100 Alu insertion polymorphisms in a heterogeneous collection of approximately 565 individuals, approximately 200 of whom were also typed for 60 microsatellites. Stripped of identifying information, correct assignment to the continent of origin (Africa, Asia, or Europe) with a mean accuracy of at least 90% required a minimum of 60 Alu markers or microsatellites and reached 99%-100% when >/=100 loci were used. Less accurate assignment (87%) to the appropriate genetic cluster was possible for a historically admixed sample from southern India. These results set a minimum for the number of markers that must be tested to make strong inferences about detecting population structure among Old World populations under ideal experimental conditions. We note that, whereas some proxies correspond crudely, if at all, to population structure, the heuristic value of others is much higher. This suggests that a more flexible framework is needed for making inferences about population structure and the utility of proxies. | [
2,
2616,
2973,
3299,
3170,
1930,
13109,
1927,
2210,
16713,
18,
43,
3044,
6640,
1927,
10652,
2659,
1977,
1942,
2392,
1920,
10956,
1942,
3394,
3626,
16534,
2436,
2859,
18,
1942,
2608,
2577,
16,
2176,
1977,
4680,
1942,
5734,
1920,
3282,
1927,
2107,
2762,
26487,
3299,
4516,
2019,
6971,
5030,
3841,
3779,
16,
2573,
6461,
16,
1930,
2644,
1942,
2311,
18,
4516,
2019,
2144,
6971,
5384,
9826,
10579,
2581,
4729,
1930,
2278,
4672,
1942,
8189,
2886,
2192,
2671,
18,
2842,
16,
1922,
2673,
9370,
16,
2176,
2278,
1998,
2715,
1942,
2782,
2144,
2671,
7555,
18,
16713,
1922,
2144,
2671,
1977,
5384,
11965,
2007,
2485,
1927,
43,
15153,
2427,
1966,
4368,
17,
1927,
17,
4853,
2014,
8639,
24740,
18,
2144,
19551,
2032,
5467,
24214,
16,
2406,
16,
2007,
2485,
1927,
13475,
1036,
16,
2427,
1966,
4407,
4677,
16,
1958,
2144,
27396,
2062,
16,
1920,
3282,
1927,
2154,
22831,
5082,
30323,
1942,
1920,
3282,
1927,
5459,
3299,
4516,
18,
7099,
16,
2176,
2258,
5433,
8827,
11756,
3053,
27396,
2062,
2032,
5409,
1930,
6305,
12281,
1927,
2671,
11965,
2037,
5459,
3299,
4516,
18,
2052,
14086,
2559,
5610,
30,
2307,
3086,
2230,
2032,
3414,
1942,
3512,
2973,
3170,
2019,
43,
10698,
2237,
1927,
4885,
16,
1942,
4663,
2237,
2112,
2973,
3170,
1998,
8397,
16,
1930,
2608,
2673,
27396,
2062,
3015,
2973,
3170,
8941,
35,
2038,
9944,
2813,
24664,
7413,
8321,
1922,
43,
8538,
4957,
1927,
3993,
4489,
1015,
3445,
16,
3993,
2191,
1927,
8566,
1985,
2222,
2601,
1007,
1958,
3276,
16069,
1036,
18,
25416,
1927,
6993,
2988,
16,
5550,
12252,
1942,
1920,
26789,
1927,
4853,
12,
8460,
16,
11624,
16,
2014,
5560,
13,
1956,
43,
2667,
4923,
1927,
2019,
3464,
3865,
9,
3414,
43,
6081,
1927,
3276,
24664,
4432,
2014,
16069,
1036,
1930,
6690,
4922,
9,
17,
2813,
9,
2469,
34,
19,
33,
2813,
6971,
1985,
2251,
18,
2941,
6305,
12252,
12,
5783,
9,
13,
1942,
1920,
4703,
3299,
4377,
1982,
3216,
1958,
43,
18011,
21694,
1919,
2983,
2037,
9257,
9288,
18,
2144,
2274,
2735,
43,
6081,
1958,
1920,
2529,
1927,
4432,
1988,
4902,
1998,
3620,
1942,
5144,
3206,
19551,
3001,
9227,
2973,
3170,
2706,
4156,
4867,
4098,
2441,
8950,
3599,
2961,
18,
2038,
4725,
1988,
16,
3417,
2673,
27396,
2062,
5593,
10289,
1954,
16,
2647,
2019,
2136,
16,
1942,
2973,
3170,
16,
1920,
25961,
3113,
1927,
4991,
1977,
4186,
2580,
18,
2052,
4015,
1988,
43,
2253,
9964,
6465,
1977,
4500,
1958,
5399,
19551,
3001,
2973,
3170,
1930,
1920,
8531,
1927,
27396,
2062,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9199562 | [
"Identification",
"of",
"proximal",
"spinal",
"muscular",
"atrophy",
"carriers",
"and",
"patients",
"by",
"analysis",
"of",
"SMNT",
" ",
"and",
"SMNC",
" ",
"gene",
"copy",
"number.",
"The",
"survival",
"motor",
"neuron",
"(SMN)",
"transcript",
"is",
"encoded",
"by",
"two",
"genes,",
"SMNT",
" ",
"and",
"SMNC.",
" ",
"The",
"autosomal",
"recessive",
"proximal",
"spinal",
"muscular",
"atrophy",
"that",
"maps",
"to",
"5q12",
"is",
"caused",
"by",
"mutations",
"in",
"the",
"SMNT",
" ",
"gene.",
"The",
"SMNT",
" ",
"gene",
"can",
"be",
"distinguished",
"from",
"the",
"SMNC",
" ",
"gene",
"by",
"base-pair",
"changes",
"in",
"exons",
"7",
"and",
"8.",
"SMNT",
" ",
"exon",
"7",
"is",
"not",
"detected",
"in",
"approximately",
"95%",
"of",
"SMA",
"cases",
"due",
"to",
"either",
"deletion",
"or",
"sequence-conversion",
"events.",
"Small",
"mutations",
"in",
"SMNT",
" ",
"now",
"have",
"been",
"identified",
"in",
"some",
"of",
"the",
"remaining",
"nondeletion",
"patients.",
"However,",
"there",
"is",
"no",
"reliable",
"quantitative",
"assay",
"for",
"SMNT,",
" ",
"to",
"distinguish",
"SMA",
"compound",
"heterozygotes",
"from",
"non-5q",
"SMA-like",
"cases",
"(phenocopies)",
"and",
"to",
"accurately",
"determine",
"carrier",
"status.",
"We",
"have",
"developed",
"a",
"quantitative",
"PCR",
"assay",
"for",
"the",
"determination",
"of",
"SMNT",
" ",
"and",
"SMNC",
" ",
"gene-copy",
"number.",
"This",
"report",
"demonstrates",
"how",
"risk",
"estimates",
"for",
"the",
"diagnosis",
"and",
"detection",
"of",
"SMA",
"carriers",
"can",
"be",
"modified",
"by",
"the",
"accurate",
"determination",
"of",
"SMNT",
" ",
"copy",
"number."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0
] | Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. The survival motor neuron (SMN) transcript is encoded by two genes, SMNT and SMNC. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMNT gene. The SMNT gene can be distinguished from the SMNC gene by base-pair changes in exons 7 and 8. SMNT exon 7 is not detected in approximately 95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMNT now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMNT, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMNT and SMNC gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMNT copy number. | [
2,
4824,
1927,
6863,
6071,
12330,
10260,
8974,
1930,
2132,
2007,
2333,
1927,
23506,
1031,
1930,
23506,
1030,
2359,
6983,
2529,
18,
1920,
3298,
4842,
7428,
12,
23506,
13,
5291,
1977,
7905,
2007,
2288,
2628,
16,
23506,
1031,
1930,
23506,
1030,
18,
1920,
13027,
13992,
6863,
6071,
12330,
10260,
1988,
7422,
1942,
25,
16886,
1028,
1977,
4189,
2007,
3527,
1922,
1920,
23506,
1031,
2359,
18,
1920,
23506,
1031,
2359,
2112,
1998,
12080,
2037,
1920,
23506,
1030,
2359,
2007,
5170,
17,
3715,
2840,
1922,
10419,
27,
1930,
28,
18,
23506,
1031,
7049,
27,
1977,
2084,
3330,
1922,
3993,
3002,
9,
1927,
11953,
2919,
2810,
1942,
3108,
5541,
2014,
3244,
17,
7309,
3916,
18,
2858,
3527,
1922,
23506,
1031,
5195,
2162,
2252,
2899,
1922,
2673,
1927,
1920,
5719,
13125,
5484,
2001,
2132,
18,
2406,
16,
2276,
1977,
2239,
7214,
4794,
3381,
1958,
23506,
1031,
16,
1942,
7279,
11953,
3547,
22910,
2037,
2447,
17,
25,
1055,
11953,
17,
3189,
2919,
12,
3037,
24724,
10984,
1918,
13,
1930,
1942,
8941,
3415,
9685,
3642,
18,
2038,
2162,
3530,
43,
4794,
3343,
3381,
1958,
1920,
7063,
1927,
23506,
1031,
1930,
23506,
1030,
2359,
17,
6983,
2529,
18,
2052,
3809,
7706,
2307,
2565,
5280,
1958,
1920,
3574,
1930,
3805,
1927,
11953,
8974,
2112,
1998,
4795,
2007,
1920,
6305,
7063,
1927,
23506,
1031,
6983,
2529,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
-100
] |
8328463 | [
"American",
"College",
"of",
"Medical",
"Genetics.",
"Prenatal",
"interphase",
"fluorescence",
"in",
"situ",
"hybridization",
"(FISH)",
"policy",
"statement."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | American College of Medical Genetics. Prenatal interphase fluorescence in situ hybridization (FISH) policy statement. | [
2,
5339,
8002,
1927,
3423,
10072,
18,
10907,
21376,
4364,
1922,
4740,
8335,
12,
5724,
13,
7299,
12977,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
11951176 | [
"Quantitative",
"trait",
"loci",
"on",
"chromosomes",
"1,",
"2,",
"3,",
"4,",
"8,",
"9,",
"11,",
"12,",
"and",
"18",
"control",
"variation",
"in",
"levels",
"of",
"T",
"and",
"B",
"lymphocyte",
"subpopulations.",
"Lymphocyte",
"subpopulation",
"levels",
"are",
"used",
"for",
"prognosis",
"and",
"monitoring",
"of",
"a",
"variety",
"of",
"human",
"diseases,",
"especially",
"those",
"with",
"an",
"infectious",
"etiology.",
"As",
"a",
"primary",
"step",
"to",
"defining",
"the",
"major",
"gene",
"variation",
"underlying",
"these",
"phenotypes,",
"we",
"conducted",
"the",
"first",
"whole-genome",
"screen",
"for",
"quantitative",
"variation",
"in",
"lymphocyte",
"count,",
"CD4",
"T",
"cell,",
"CD8",
"T",
"cell,",
"B",
"cell,",
"and",
"natural",
"killer",
"cell",
"numbers,",
"as",
"well",
"as",
"CD4:CD8",
"ratio.",
"The",
"screen",
"was",
"performed",
"in",
"15",
"of",
"the",
"CEPH",
"families",
"that",
"form",
"the",
"main",
"human",
"genome",
"genetic",
"project",
"mapping",
"resource.",
"Quantitative-trait",
"loci",
"(QTLs)",
"that",
"account",
"for",
"significant",
"proportions",
"of",
"the",
"phenotypic",
"variance",
"of",
"lymphocyte",
"subpopulations",
"were",
"detected",
"on",
"chromosomes",
"1,",
"2,",
"3,",
"4,",
"8,",
"9,",
"11,",
"12,",
"and",
"18.",
"The",
"most",
"significant",
"QTL",
"found",
"was",
"for",
"CD4",
"levels",
"on",
"chromosome",
"8",
"(empirical",
"P=.00005).",
"Two",
"regions",
"of",
"chromosome",
"4",
"showed",
"significant",
"linkage",
"to",
"CD4:CD8",
"ratio",
"(empirical",
"P=.00007",
"and",
"P=.003).",
"A",
"QTL",
"for",
"the",
"highly",
"correlated",
"measures",
"of",
"CD4",
"and",
"CD19",
"levels",
"colocalized",
"at",
"18q21",
"(both",
"P=.003).",
"Similarly,",
"a",
"shared",
"region",
"of",
"chromosome",
"1",
"was",
"linked",
"to",
"CD8",
"and",
"CD19",
"levels",
"(P=.0001",
"and",
"P=.002,",
"respectively).",
"Several",
"of",
"the",
"identified",
"chromosome",
"regions",
"are",
"likely",
"to",
"harbor",
"polymorphic",
"candidate",
"genes",
"responsible",
"for",
"these",
"important",
"human",
"phenotypes.",
"Their",
"discovery",
"has",
"important",
"implications",
"for",
"understanding",
"the",
"generation",
"of",
"the",
"immune",
"repertoire",
"and",
"understanding",
"immune-system",
"homeostasis.",
"More",
"generally,",
"these",
"data",
"show",
"the",
"power",
"of",
"an",
"integrated",
"human",
"gene-mapping",
"approach",
"for",
"heritable",
"molecular",
"phenotypes,",
"using",
"large",
"pedigrees",
"that",
"have",
"been",
"extensively",
"genotyped."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Quantitative trait loci on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18 control variation in levels of T and B lymphocyte subpopulations. Lymphocyte subpopulation levels are used for prognosis and monitoring of a variety of human diseases, especially those with an infectious etiology. As a primary step to defining the major gene variation underlying these phenotypes, we conducted the first whole-genome screen for quantitative variation in lymphocyte count, CD4 T cell, CD8 T cell, B cell, and natural killer cell numbers, as well as CD4:CD8 ratio. The screen was performed in 15 of the CEPH families that form the main human genome genetic project mapping resource. Quantitative-trait loci (QTLs) that account for significant proportions of the phenotypic variance of lymphocyte subpopulations were detected on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18. The most significant QTL found was for CD4 levels on chromosome 8 (empirical P=.00005). Two regions of chromosome 4 showed significant linkage to CD4:CD8 ratio (empirical P=.00007 and P=.003). A QTL for the highly correlated measures of CD4 and CD19 levels colocalized at 18q21 (both P=.003). Similarly, a shared region of chromosome 1 was linked to CD8 and CD19 levels (P=.0001 and P=.002, respectively). Several of the identified chromosome regions are likely to harbor polymorphic candidate genes responsible for these important human phenotypes. Their discovery has important implications for understanding the generation of the immune repertoire and understanding immune-system homeostasis. More generally, these data show the power of an integrated human gene-mapping approach for heritable molecular phenotypes, using large pedigrees that have been extensively genotyped. | [
2,
4794,
8823,
6971,
1990,
8597,
21,
16,
22,
16,
23,
16,
24,
16,
28,
16,
29,
16,
2513,
16,
2369,
16,
1930,
2654,
2285,
4516,
1922,
2428,
1927,
62,
1930,
44,
10009,
14349,
18,
10009,
15916,
2428,
2032,
2251,
1958,
6573,
1930,
5378,
1927,
43,
5386,
1927,
2616,
3902,
16,
4369,
2690,
1956,
1925,
7465,
10383,
18,
1966,
43,
3065,
3537,
1942,
11266,
1920,
3044,
2359,
4516,
5030,
2144,
6568,
16,
2038,
3609,
1920,
2561,
4292,
17,
3843,
7053,
1958,
4794,
4516,
1922,
10009,
6500,
16,
4095,
62,
2024,
16,
5659,
62,
2024,
16,
44,
2024,
16,
1930,
4613,
16644,
2024,
4630,
16,
1966,
2486,
1966,
4095,
30,
5659,
3400,
18,
1920,
7053,
1982,
2593,
1922,
2461,
1927,
1920,
17008,
1023,
5767,
1988,
2386,
1920,
2730,
2616,
3843,
3299,
5539,
7084,
7965,
18,
4794,
17,
8823,
6971,
12,
20182,
13,
1988,
5042,
1958,
2228,
9766,
1927,
1920,
8189,
5623,
1927,
10009,
14349,
1985,
3330,
1990,
8597,
21,
16,
22,
16,
23,
16,
24,
16,
28,
16,
29,
16,
2513,
16,
2369,
16,
1930,
2654,
18,
1920,
2501,
2228,
12541,
2435,
1982,
1958,
4095,
2428,
1990,
5597,
28,
12,
9203,
58,
33,
18,
28547,
1015,
13,
18,
2288,
3451,
1927,
5597,
24,
2594,
2228,
8611,
1942,
4095,
30,
5659,
3400,
12,
9203,
58,
33,
18,
28547,
1027,
1930,
58,
33,
18,
10438,
13,
18,
43,
12541,
1958,
1920,
3626,
4374,
3975,
1927,
4095,
1930,
15812,
2428,
21602,
2019,
2654,
23470,
1009,
12,
2321,
58,
33,
18,
10438,
13,
18,
4852,
16,
43,
7115,
3031,
1927,
5597,
21,
1982,
4624,
1942,
5659,
1930,
15812,
2428,
12,
58,
33,
18,
6060,
1930,
58,
33,
18,
9299,
16,
2763,
13,
18,
2980,
1927,
1920,
2899,
5597,
3451,
2032,
3205,
1942,
14355,
14240,
6610,
2628,
5061,
1958,
2144,
2715,
2616,
6568,
18,
2310,
7139,
2258,
2715,
7020,
1958,
4339,
1920,
4841,
1927,
1920,
3743,
15344,
1930,
4339,
3743,
17,
2433,
7622,
18,
2253,
4933,
16,
2144,
2230,
2146,
1920,
4215,
1927,
1925,
6714,
2616,
2359,
17,
7084,
2998,
1958,
22851,
3272,
6568,
16,
2193,
3103,
22336,
1036,
1988,
2162,
2252,
9172,
14401,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9463309 | [
"The",
"haptoglobin-gene",
"deletion",
"responsible",
"for",
"anhaptoglobinemia.",
"We",
"have",
"found",
"an",
"allelic",
"deletion",
"of",
"the",
"haptoglobin",
" ",
"(Hp)",
" ",
"gene",
"from",
"an",
"individual",
"with",
"anhaptoglobinemia.",
"The",
"Hp",
"gene",
"cluster",
"consists",
"of",
"coding",
"regions",
"of",
"the",
"alpha",
"chain",
"and",
"beta",
"chain",
"of",
"the",
"haptoglobin",
" ",
"gene",
"(Hp)",
" ",
"and",
"of",
"the",
"alpha",
"chain",
"and",
"beta",
"chain",
"of",
"the",
"haptoglobin-related",
"gene",
" ",
"(Hpr),",
" ",
"in",
"tandem",
"from",
"the",
"5'",
"side.",
"Southern",
"blot",
"and",
"PCR",
"analyses",
"have",
"indicated",
"that",
"the",
"individual",
"with",
"anhaptoglobinemia",
"was",
"homozygous",
"for",
"the",
"gene",
"deletion",
"and",
"that",
"the",
"gene",
"deletion",
"was",
"included",
"at",
"least",
"from",
"the",
"promoter",
"region",
"of",
"Hp",
"to",
"Hpr",
"alpha",
" ",
"but",
"not",
"to",
"Hpr",
"beta",
" ",
"(Hpdel).",
"In",
"addition,",
"we",
"found",
"seven",
"individuals",
"with",
"hypohaptoglobinemia",
"in",
"three",
"families,",
"and",
"the",
"genotypes",
"of",
"six",
"of",
"the",
"seven",
"individuals",
"were",
"found",
"to",
"be",
"Hp2/Hpdel.",
"The",
"phenotypes",
"and",
"genotypes",
"in",
"one",
"of",
"these",
"three",
"families",
"showed",
"the",
"father",
"to",
"be",
"hypohaptoglobinemic",
"(Hp2)",
" ",
"and",
"Hp2/Hpdel,",
"the",
"mother",
"to",
"be",
"Hp2-1",
" ",
"and",
"Hp1/Hp2,",
"one",
"of",
"the",
"two",
"children",
"to",
"be",
"hypohaptoglobinemic",
"(Hp2)",
" ",
"and",
"Hp2/Hpdel,",
"and",
"the",
"other",
"child",
"to",
"be",
"Hp1",
" ",
"and",
"Hp1/Hpdel,",
"showing",
"an",
"anomalous",
"inheritance",
"of",
"Hp",
"phenotypes",
"in",
"the",
"child",
"with",
"Hp1.",
" ",
"The",
"Hp2/Hpdel",
"individuals",
"had",
"an",
"extremely",
"low",
"level",
"of",
"Hp",
"(mean+/-SD",
"=",
"0.049+/-0.",
"043",
"mg/ml;",
"n=6),",
"compared",
"with",
"the",
"level",
"(1.64+/-1.07",
"mg/ml)",
"obtained",
"from",
"52",
"healthy",
"volunteers",
"having",
"phenotype",
"Hp2,",
" ",
"whereas",
"the",
"serum",
"Hp",
"level",
"of",
"an",
"individual",
"with",
"Hp1/Hpdel",
"was",
"0.50",
"mg/ml,",
"which",
"was",
"approximately",
"half",
"the",
"level",
"of",
"Hp",
"in",
"control",
"sera",
"from",
"the",
"Hp1",
" ",
"phenotype",
"(1.26+/-0.33",
"mg/ml;",
"n=9),",
"showing",
"a",
"gene-dosage",
"effect.",
"The",
"other",
"allele",
"(Hp2)",
" ",
"of",
"individuals",
"with",
"Hp2/Hpdel",
"was",
"found",
"to",
"have,",
"in",
"all",
"exons,",
"no",
"mutation,",
"by",
"DNA",
"sequencing.",
"On",
"the",
"basis",
"of",
"the",
"present",
"study,",
"the",
"mechanism",
"of",
"anhaptoglobinemia",
"and",
"the",
"mechanism",
"of",
"anomalous",
"inheritance",
"of",
"Hp",
"phenotypes",
"were",
"well",
"explained.",
"However,",
"the",
"mechanism",
"of",
"hypohaptoglobinemia",
"remains",
"unknown."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The haptoglobin-gene deletion responsible for anhaptoglobinemia. We have found an allelic deletion of the haptoglobin (Hp) gene from an individual with anhaptoglobinemia. The Hp gene cluster consists of coding regions of the alpha chain and beta chain of the haptoglobin gene (Hp) and of the alpha chain and beta chain of the haptoglobin-related gene (Hpr), in tandem from the 5' side. Southern blot and PCR analyses have indicated that the individual with anhaptoglobinemia was homozygous for the gene deletion and that the gene deletion was included at least from the promoter region of Hp to Hpr alpha but not to Hpr beta (Hpdel). In addition, we found seven individuals with hypohaptoglobinemia in three families, and the genotypes of six of the seven individuals were found to be Hp2/Hpdel. The phenotypes and genotypes in one of these three families showed the father to be hypohaptoglobinemic (Hp2) and Hp2/Hpdel, the mother to be Hp2-1 and Hp1/Hp2, one of the two children to be hypohaptoglobinemic (Hp2) and Hp2/Hpdel, and the other child to be Hp1 and Hp1/Hpdel, showing an anomalous inheritance of Hp phenotypes in the child with Hp1. The Hp2/Hpdel individuals had an extremely low level of Hp (mean+/-SD = 0.049+/-0. 043 mg/ml; n=6), compared with the level (1.64+/-1.07 mg/ml) obtained from 52 healthy volunteers having phenotype Hp2, whereas the serum Hp level of an individual with Hp1/Hpdel was 0.50 mg/ml, which was approximately half the level of Hp in control sera from the Hp1 phenotype (1.26+/-0.33 mg/ml; n=9), showing a gene-dosage effect. The other allele (Hp2) of individuals with Hp2/Hpdel was found to have, in all exons, no mutation, by DNA sequencing. On the basis of the present study, the mechanism of anhaptoglobinemia and the mechanism of anomalous inheritance of Hp phenotypes were well explained. However, the mechanism of hypohaptoglobinemia remains unknown. | [
2,
1920,
29683,
7856,
17,
2359,
5541,
5061,
1958,
1925,
2722,
2410,
7856,
3847,
18,
2038,
2162,
2435,
1925,
13045,
5541,
1927,
1920,
29683,
7856,
12,
4688,
13,
2359,
2037,
1925,
2725,
1956,
1925,
2722,
2410,
7856,
3847,
18,
1920,
4688,
2359,
4377,
7543,
1927,
5804,
3451,
1927,
1920,
4595,
4659,
1930,
4666,
4659,
1927,
1920,
29683,
7856,
2359,
12,
4688,
13,
1930,
1927,
1920,
4595,
4659,
1930,
4666,
4659,
1927,
1920,
29683,
7856,
17,
2712,
2359,
12,
18542,
13,
16,
1922,
10361,
2037,
1920,
25,
11,
4159,
18,
9257,
4918,
1930,
3343,
3247,
2162,
3391,
1988,
1920,
2725,
1956,
1925,
2722,
2410,
7856,
3847,
1982,
9419,
1958,
1920,
2359,
5541,
1930,
1988,
1920,
2359,
5541,
1982,
3063,
2019,
3464,
2037,
1920,
4465,
3031,
1927,
4688,
1942,
18542,
4595,
2308,
2084,
1942,
18542,
4666,
12,
4688,
16878,
13,
18,
1922,
2459,
16,
2038,
2435,
5260,
3445,
1956,
14395,
2722,
2410,
7856,
3847,
1922,
2559,
5767,
16,
1930,
1920,
7059,
1927,
3798,
1927,
1920,
5260,
3445,
1985,
2435,
1942,
1998,
4688,
1028,
19,
4688,
16878,
18,
1920,
6568,
1930,
7059,
1922,
2340,
1927,
2144,
2559,
5767,
2594,
1920,
14854,
1942,
1998,
14395,
2722,
2410,
7856,
4197,
12,
4688,
1028,
13,
1930,
4688,
1028,
19,
4688,
16878,
16,
1920,
7999,
1942,
1998,
4688,
1028,
17,
21,
1930,
27575,
19,
4688,
1028,
16,
2340,
1927,
1920,
2288,
3069,
1942,
1998,
14395,
2722,
2410,
7856,
4197,
12,
4688,
1028,
13,
1930,
4688,
1028,
19,
4688,
16878,
16,
1930,
1920,
2303,
2748,
1942,
1998,
27575,
1930,
27575,
19,
4688,
16878,
16,
4570,
1925,
20577,
15762,
1927,
4688,
6568,
1922,
1920,
2748,
1956,
27575,
18,
1920,
4688,
1028,
19,
4688,
16878,
3445,
2430,
1925,
8113,
2330,
2237,
1927,
4688,
12,
2667,
15,
19,
17,
4035,
33,
20,
18,
25428,
15,
19,
17,
20,
18,
25878,
2786,
19,
2646,
31,
56,
33,
26,
13,
16,
2452,
1956,
1920,
2237,
12,
21,
18,
4723,
15,
19,
17,
21,
18,
6627,
2786,
19,
2646,
13,
2926,
2037,
4764,
4097,
9701,
4537,
4629,
4688,
1028,
16,
3417,
1920,
3256,
4688,
2237,
1927,
1925,
2725,
1956,
27575,
19,
4688,
16878,
1982,
20,
18,
2761,
2786,
19,
2646,
16,
2154,
1982,
3993,
4768,
1920,
2237,
1927,
4688,
1922,
2285,
9779,
2037,
1920,
27575,
4629,
12,
21,
18,
3179,
15,
19,
17,
20,
18,
3401,
2786,
19,
2646,
31,
56,
33,
29,
13,
16,
4570,
43,
2359,
17,
9998,
2495,
18,
1920,
2303,
5465,
12,
4688,
1028,
13,
1927,
3445,
1956,
4688,
1028,
19,
4688,
16878,
1982,
2435,
1942,
2162,
16,
1922,
2136,
10419,
16,
2239,
3979,
16,
2007,
2678,
4754,
18,
1990,
1920,
4859,
1927,
1920,
2481,
2161,
16,
1920,
2856,
1927,
1925,
2722,
2410,
7856,
3847,
1930,
1920,
2856,
1927,
20577,
15762,
1927,
4688,
6568,
1985,
2486,
6094,
18,
2406,
16,
1920,
2856,
1927,
14395,
2722,
2410,
7856,
3847,
4497,
5435,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
12618959 | [
"Autosomal",
"recessive",
"HEM/Greenberg",
"skeletal",
"dysplasia",
"is",
"caused",
"by",
"3",
"beta-hydroxysterol",
"delta",
"14-reductase",
"deficiency",
"due",
"to",
"mutations",
"in",
"the",
"lamin",
"B",
"receptor",
" ",
"gene.",
"Hydrops-ectopic",
"calcification-\"moth-eaten\"",
"(HEM)",
"or",
"Greenberg",
"skeletal",
"dysplasia",
"is",
"an",
"autosomal",
"recessive",
"chondrodystrophy",
"with",
"a",
"lethal",
"course,",
"characterized",
"by",
"fetal",
"hydrops,",
"short",
"limbs,",
"and",
"abnormal",
"chondro-osseous",
"calcification.",
"We",
"found",
"elevated",
"levels",
"of",
"cholesta-8,14-dien-3beta-ol",
"in",
"cultured",
"skin",
"fibroblasts",
"of",
"an",
"18-wk-old",
"fetus",
"with",
"HEM,",
"compatible",
"with",
"a",
"deficiency",
"of",
"the",
"cholesterol",
"biosynthetic",
"enzyme",
"3beta-hydroxysterol",
"delta(14)-reductase",
".",
"Sequence",
"analysis",
"of",
"two",
"candidate",
"genes",
"encoding",
"putative",
"human",
"sterol",
"delta(14)-reductases",
"(TM7SF2",
"and",
"LBR)",
"identified",
"a",
"homozygous",
"1599-1605TCTTCTA-->CTAGAAG",
" ",
"substitution",
"in",
"exon",
"13",
"of",
"the",
"LBR",
"human",
"sterol",
"delta(14)-reductases",
" ",
"(",
"TM7SF2",
" ",
"and",
"LBR",
")",
"identified",
"a",
"homozygous",
"1599-1605TCTTCTA-->CTAGAAG",
"substitution",
"in",
"exon",
"13",
"of",
"the",
"LBR",
"gene",
"encoding",
"the",
"lamin",
"B",
"receptor,",
"which",
"results",
"in",
"a",
"truncated",
"protein.",
"Functional",
"complementation",
"of",
"the",
"HEM",
"cells",
"by",
"transfection",
"with",
"control",
"LBR",
"cDNA",
"confirmed",
"that",
"LBR",
" ",
"encoded",
"the",
"defective",
"sterol",
"delta(14)-reductase.",
"Mutations",
"in",
"LBR",
" ",
"recently",
"have",
"been",
"reported",
"also",
"to",
"cause",
"Pelger-Huët",
"anomaly,",
"an",
"autosomal",
"dominant",
"trait",
"characterized",
"by",
"hypolobulated",
"nuclei",
"and",
"abnormal",
"chromatin",
"structure",
"in",
"granulocytes.",
"The",
"fact",
"that",
"the",
"healthy",
"mother",
"of",
"the",
"fetus",
"showed",
"hypolobulated",
"nuclei",
"in",
"60%",
"of",
"her",
"granulocytes",
"confirms",
"that",
"classic",
"Pelger-Huët",
"anomaly",
"represents",
"the",
"heterozygous",
"state",
"of",
"3beta-hydroxysterol",
"delta(14)-reductase",
" ",
"deficiency."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
1,
1,
2,
2,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0
] | Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene. Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification. We found elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin fibroblasts of an 18-wk-old fetus with HEM, compatible with a deficiency of the cholesterol biosynthetic enzyme 3beta-hydroxysterol delta(14)-reductase . Sequence analysis of two candidate genes encoding putative human sterol delta(14)-reductases (TM7SF2 and LBR) identified a homozygous 1599-1605TCTTCTA-->CTAGAAG substitution in exon 13 of the LBR human sterol delta(14)-reductases ( TM7SF2 and LBR ) identified a homozygous 1599-1605TCTTCTA-->CTAGAAG substitution in exon 13 of the LBR gene encoding the lamin B receptor, which results in a truncated protein. Functional complementation of the HEM cells by transfection with control LBR cDNA confirmed that LBR encoded the defective sterol delta(14)-reductase. Mutations in LBR recently have been reported also to cause Pelger-Huët anomaly, an autosomal dominant trait characterized by hypolobulated nuclei and abnormal chromatin structure in granulocytes. The fact that the healthy mother of the fetus showed hypolobulated nuclei in 60% of her granulocytes confirms that classic Pelger-Huët anomaly represents the heterozygous state of 3beta-hydroxysterol delta(14)-reductase deficiency. | [
2,
13027,
13992,
3243,
19,
4524,
7519,
7345,
14095,
1977,
4189,
2007,
23,
4666,
17,
8275,
2156,
6506,
1024,
9649,
2607,
17,
11386,
6179,
2810,
1942,
3527,
1922,
1920,
7962,
44,
3148,
2359,
18,
3290,
2523,
17,
11092,
14640,
17,
6,
6798,
17,
13619,
1917,
6,
12,
3243,
13,
2014,
4524,
7519,
7345,
14095,
1977,
1925,
13027,
13992,
22480,
14458,
2156,
6825,
1956,
43,
10470,
4914,
16,
4378,
2007,
5944,
3290,
2523,
16,
3662,
14054,
16,
1930,
4552,
22480,
17,
29251,
14640,
18,
2038,
2435,
4664,
2428,
1927,
21211,
1019,
17,
28,
16,
2607,
17,
8769,
1022,
17,
6341,
9215,
17,
2865,
1922,
4789,
4407,
7001,
1927,
1925,
2654,
17,
11939,
17,
4156,
15722,
1956,
3243,
16,
11290,
1956,
43,
6179,
1927,
1920,
5463,
14041,
4113,
6341,
9215,
17,
8275,
2156,
6506,
1024,
9649,
12,
2607,
13,
17,
11386,
18,
3244,
2333,
1927,
2288,
6610,
2628,
5797,
6770,
2616,
20408,
9649,
12,
2607,
13,
17,
11386,
1036,
12,
5072,
1027,
1036,
6680,
1930,
8750,
1005,
13,
2899,
43,
9419,
14486,
1026,
17,
9608,
1015,
6916,
3519,
2341,
1019,
17,
17,
34,
19038,
26378,
6636,
1922,
7049,
2590,
1927,
1920,
8750,
1005,
2616,
20408,
9649,
12,
2607,
13,
17,
11386,
1036,
12,
5072,
1027,
1036,
6680,
1930,
8750,
1005,
13,
2899,
43,
9419,
14486,
1026,
17,
9608,
1015,
6916,
3519,
2341,
1019,
17,
17,
34,
19038,
26378,
6636,
1922,
7049,
2590,
1927,
1920,
8750,
1005,
2359,
5797,
1920,
7962,
44,
3148,
16,
2154,
2274,
1922,
43,
9530,
2213,
18,
3183,
17465,
1927,
1920,
3243,
2094,
2007,
6496,
1956,
2285,
8750,
1005,
5885,
3982,
1988,
8750,
1005,
7905,
1920,
9785,
20408,
9649,
12,
2607,
13,
17,
11386,
18,
3527,
1922,
8750,
1005,
3998,
2162,
2252,
2568,
2222,
1942,
3936,
7874,
4938,
17,
5897,
1946,
20950,
16,
1925,
13027,
6379,
8823,
4378,
2007,
14395,
6012,
17909,
15793,
6742,
1930,
4552,
6338,
3170,
1922,
22144,
18,
1920,
2371,
1988,
1920,
4097,
7999,
1927,
1920,
15722,
2594,
14395,
6012,
17909,
15793,
6742,
1922,
3276,
9,
1927,
3656,
22144,
12858,
1988,
12211,
7874,
4938,
17,
5897,
1946,
20950,
4972,
1920,
9589,
3360,
1927,
6341,
9215,
17,
8275,
2156,
6506,
1024,
9649,
12,
2607,
13,
17,
11386,
6179,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
2,
2,
2,
2,
2,
2,
2,
0,
1,
2,
2,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
0,
0,
-100
] |
10915611 | [
"Rare",
"etiology",
"of",
"autosomal",
"recessive",
"disease",
"in",
"a",
"child",
"with",
"noncarrier",
"parents.",
"A",
"child",
"with",
"maple",
"syrup",
"urine",
"disease",
"type",
"2",
"(MSUD2)",
"was",
"found",
"to",
"be",
"homozygous",
"for",
"a",
"10-bp",
"MSUD2",
"-gene",
"deletion",
"on",
"chromosome",
"1.",
"Both",
"purported",
"parents",
"were",
"tested,",
"and",
"neither",
"carries",
"the",
"gene",
"deletion.",
"Polymorphic",
"simple-sequence",
"repeat",
"analyses",
"at",
"15",
"loci",
"on",
"chromosome",
"1",
"and",
"at",
"16",
"loci",
"on",
"other",
"chromosomes",
"confirmed",
"parentage",
"and",
"revealed",
"that",
"a",
"de",
"novo",
"mutation",
"prior",
"to",
"maternal",
"meiosis",
"I,",
"followed",
"by",
"nondisjunction",
"in",
"maternal",
"meiosis",
"II,",
"resulted",
"in",
"an",
"oocyte",
"with",
"two",
"copies",
"of",
"the",
"de",
"novo",
"mutant",
"allele.",
"Fertilization",
"by",
"a",
"sperm",
"that",
"did",
"not",
"carry",
"a",
"paternal",
"chromosome",
"1",
"or",
"subsequent",
"mitotic",
"loss",
"of",
"the",
"paternal",
"chromosome",
"1",
"resulted",
"in",
"the",
"propositus",
"inheriting",
"two",
"mutant",
"MSUD2",
" ",
"alleles",
"on",
"two",
"maternal",
"number",
"1",
"chromosomes."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0
] | Rare etiology of autosomal recessive disease in a child with noncarrier parents. A child with maple syrup urine disease type 2 (MSUD2) was found to be homozygous for a 10-bp MSUD2 -gene deletion on chromosome 1. Both purported parents were tested, and neither carries the gene deletion. Polymorphic simple-sequence repeat analyses at 15 loci on chromosome 1 and at 16 loci on other chromosomes confirmed parentage and revealed that a de novo mutation prior to maternal meiosis I, followed by nondisjunction in maternal meiosis II, resulted in an oocyte with two copies of the de novo mutant allele. Fertilization by a sperm that did not carry a paternal chromosome 1 or subsequent mitotic loss of the paternal chromosome 1 resulted in the propositus inheriting two mutant MSUD2 alleles on two maternal number 1 chromosomes. | [
2,
5844,
10383,
1927,
13027,
13992,
2573,
1922,
43,
2748,
1956,
9341,
3994,
3453,
5853,
18,
43,
2748,
1956,
4446,
1952,
11458,
3481,
6960,
2573,
2601,
22,
12,
3012,
2009,
1028,
13,
1982,
2435,
1942,
1998,
9419,
1958,
43,
2119,
17,
4149,
3012,
2009,
1028,
17,
2359,
5541,
1990,
5597,
21,
18,
2321,
25945,
2718,
1919,
5853,
1985,
3620,
16,
1930,
7132,
16252,
1920,
2359,
5541,
18,
14240,
5288,
17,
3244,
6865,
3247,
2019,
2461,
6971,
1990,
5597,
21,
1930,
2019,
2641,
6971,
1990,
2303,
8597,
3982,
6162,
2170,
1930,
3404,
1988,
43,
2028,
9441,
3979,
3432,
1942,
5509,
17979,
51,
16,
3489,
2007,
13125,
1937,
12723,
2236,
1922,
5509,
17979,
2890,
16,
4306,
1922,
1925,
13647,
1956,
2288,
9425,
1927,
1920,
2028,
9441,
3606,
5465,
18,
14493,
2007,
43,
6283,
1988,
2811,
2084,
9875,
43,
16046,
5597,
21,
2014,
4521,
9566,
3257,
1927,
1920,
16046,
5597,
21,
4306,
1922,
1920,
13398,
7831,
7232,
3658,
2288,
3606,
3012,
2009,
1028,
7096,
1990,
2288,
5509,
2529,
21,
8597,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9443866 | [
"Ataxia-telangiectasia:",
"identification",
"and",
"detection",
"of",
"founder-effect",
"mutations",
"in",
"the",
"ATM",
" ",
"gene",
"in",
"ethnic",
"populations.",
"To",
"facilitate",
"the",
"evaluation",
"of",
"ATM",
" ",
"heterozygotes",
"for",
"susceptibility",
"to",
"other",
"diseases,",
"such",
"as",
"breast",
"cancer,",
"we",
"have",
"attempted",
"to",
"define",
"the",
"most",
"common",
"mutations",
"and",
"their",
"frequencies",
"in",
"ataxia-telangiectasia",
"(A-T)",
"homozygotes",
"from",
"10",
"ethnic",
"populations.",
"Both",
"genomic",
"mutations",
"and",
"their",
"effects",
"on",
"cDNA",
"were",
"characterized.",
"Protein-truncation",
"testing",
"of",
"the",
"entire",
"ATM",
" ",
"cDNA",
"detected",
"92",
"(66%)",
"truncating",
"mutations",
"in",
"140",
"mutant",
"alleles",
"screened.",
"The",
"haplotyping",
"of",
"patients",
"with",
"identical",
"mutations",
"indicates",
"that",
"almost",
"all",
"of",
"these",
"represent",
"common",
"ancestry",
"and",
"that",
"very",
"few",
"spontaneously",
"recurring",
"ATM",
" ",
"mutations",
"exist.",
"Assays",
"requiring",
"minimal",
"amounts",
"of",
"genomic",
"DNA",
"were",
"designed",
"to",
"allow",
"rapid",
"screening",
"for",
"common",
"ethnic",
"mutations.",
"These",
"rapid",
"assays",
"detected",
"mutations",
"in",
"76%",
"of",
"Costa",
"Rican",
"patients",
"(3),",
"50%",
"of",
"Norwegian",
"patients",
"(1),",
"25%",
"of",
"Polish",
"patients",
"(4),",
"and",
"14%",
"of",
"Italian",
"patients",
"(1),",
"as",
"well",
"as",
"in",
"patients",
"of",
"Amish/Mennonite",
"and",
"Irish",
"English",
"backgrounds.",
"Additional",
"mutations",
"were",
"observed",
"in",
"Japanese,",
"Utah",
"Mormon,",
"and",
"African",
"American",
"patients.",
"These",
"assays",
"should",
"facilitate",
"screening",
"for",
"A-T",
"heterozygotes",
"in",
"the",
"populations",
"studied."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied. | [
2,
17698,
17,
30512,
6646,
30,
4824,
1930,
3805,
1927,
21350,
17,
2495,
3527,
1922,
1920,
7513,
2359,
1922,
8639,
4098,
18,
1942,
6628,
1920,
4391,
1927,
7513,
22910,
1958,
6461,
1942,
2303,
3902,
16,
2427,
1966,
3739,
2539,
16,
2038,
2162,
11189,
1942,
7425,
1920,
2501,
3059,
3527,
1930,
2310,
6458,
1922,
17698,
17,
30512,
6646,
12,
43,
17,
62,
13,
22686,
2037,
2119,
8639,
4098,
18,
2321,
4935,
3527,
1930,
2310,
2564,
1990,
5885,
1985,
4378,
18,
2213,
17,
18802,
4213,
1927,
1920,
5346,
7513,
5885,
3330,
6224,
12,
4970,
9,
13,
7847,
2287,
3527,
1922,
8949,
3606,
7096,
8582,
18,
1920,
22435,
5518,
1941,
1927,
2132,
1956,
6119,
3527,
4538,
1988,
5365,
2136,
1927,
2144,
3015,
3059,
15419,
1930,
1988,
3345,
3855,
12753,
30489,
7513,
3527,
5516,
18,
4614,
8887,
6343,
6222,
1927,
4935,
2678,
1985,
4609,
1942,
3235,
4052,
4449,
1958,
3059,
8639,
3527,
18,
2144,
4052,
4614,
3330,
3527,
1922,
5439,
9,
1927,
24051,
18091,
1928,
2132,
12,
23,
13,
16,
2761,
9,
1927,
21190,
2132,
12,
21,
13,
16,
2637,
9,
1927,
24779,
2132,
12,
24,
13,
16,
1930,
2607,
9,
1927,
15922,
2132,
12,
21,
13,
16,
1966,
2486,
1966,
1922,
2132,
1927,
15665,
6150,
19,
3925,
29591,
2394,
1930,
17187,
1023,
8998,
15650,
18,
3281,
3527,
1985,
2528,
1922,
10405,
16,
28320,
2803,
3947,
16,
1930,
7050,
5339,
2132,
18,
2144,
4614,
3066,
6628,
4449,
1958,
43,
17,
62,
22910,
1922,
1920,
4098,
3942,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8956037 | [
"A",
"novel",
"deletion/inversion",
"mutation",
"in",
"the",
"low-density",
"lipoprotein",
"receptor",
" ",
"gene",
"as",
"a",
"cause",
"of",
"heterozygous",
"familial",
"hypercholesterolemia.",
"A",
"combined",
"deletion/inversion",
"rearrangement",
"of",
"the",
"LDL",
" ",
"receptor",
"gene",
"was",
"discovered",
"in",
"a",
"Finnish",
"patient",
"with",
"heterozygous",
"familial",
"hypercholesterolemia",
"(FH).",
"Sequence",
"analysis",
"of",
"the",
"mutated",
"allele",
"revealed",
"an",
"insertion",
"of",
"4",
"nucleotides",
"in",
"exon",
"11,",
"caused",
"by",
"a",
"combined",
"deletion",
"and",
"insertion",
"event",
"replacing",
"a",
"13-bp",
"segment",
"of",
"the",
"normal",
"exon",
"11",
"sequence",
"of",
"the",
"LDL",
"receptor",
"gene",
"by",
"a",
"17-bp",
"stretch",
"of",
"new",
"sequence",
"at",
"the",
"deletion",
"breakpoint.",
"The",
"inserted",
"sequence",
"was",
"identical",
"to",
"the",
"normal",
"exon",
"9",
"sequence",
"of",
"the",
"LDL",
" ",
"receptor",
"gene",
"from",
"nt1225",
"to",
"nt1241",
"inserted",
"in",
"an",
"inverted",
"orientation.",
"This",
"defect",
"causes",
"a",
"translational",
"frameshift",
"after",
"amino",
"acid",
"525",
"(glycine)",
"and",
"leads",
"to",
"a",
"premature",
"termination",
"codon",
"at",
"amino",
"acid",
"position",
"538",
".",
"Analysis",
"of",
"reverse",
"transcriptase-PCR",
"products",
"from",
"total",
"RNA",
"extracted",
"from",
"cultured",
"fibroblasts",
"revealed",
"only",
"transcripts",
"encoded",
"by",
"the",
"normal",
"allele.",
"This",
"finding",
"was",
"consistent",
"with",
"the",
"reduced",
"functional",
"activity",
"of",
"the",
"LDL",
" ",
"receptor",
"found",
"in",
"the",
"fibroblasts",
"of",
"the",
"patient",
"to",
"levels",
"less",
"than",
"50%",
"of",
"those",
"in",
"normal",
"cells.",
"In",
"conclusion,",
"we",
"have",
"identified",
"a",
"complex",
"and",
"hitherto",
"unreported",
"type",
"of",
"rearrangement",
"of",
"the",
"human",
"LDL",
" ",
"receptor",
"gene.",
"The",
"precise",
"mechanism",
"of",
"this",
"mutation",
"(designated",
"as",
"FH-Jalasjärvi)",
"remains",
"obscure,",
"although",
"it",
"may",
"involve",
"complex",
"loop",
"formation",
"by",
"interaction",
"of",
"complementary",
"sequences",
"present",
"in",
"the",
"mutation",
"breakpoints",
"and",
"their",
"immediate",
"flanking",
"regions."
] | [
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A novel deletion/inversion mutation in the low-density lipoprotein receptor gene as a cause of heterozygous familial hypercholesterolemia. A combined deletion/inversion rearrangement of the LDL receptor gene was discovered in a Finnish patient with heterozygous familial hypercholesterolemia (FH). Sequence analysis of the mutated allele revealed an insertion of 4 nucleotides in exon 11, caused by a combined deletion and insertion event replacing a 13-bp segment of the normal exon 11 sequence of the LDL receptor gene by a 17-bp stretch of new sequence at the deletion breakpoint. The inserted sequence was identical to the normal exon 9 sequence of the LDL receptor gene from nt1225 to nt1241 inserted in an inverted orientation. This defect causes a translational frameshift after amino acid 525 (glycine) and leads to a premature termination codon at amino acid position 538 . Analysis of reverse transcriptase-PCR products from total RNA extracted from cultured fibroblasts revealed only transcripts encoded by the normal allele. This finding was consistent with the reduced functional activity of the LDL receptor found in the fibroblasts of the patient to levels less than 50% of those in normal cells. In conclusion, we have identified a complex and hitherto unreported type of rearrangement of the human LDL receptor gene. The precise mechanism of this mutation (designated as FH-Jalasjärvi) remains obscure, although it may involve complex loop formation by interaction of complementary sequences present in the mutation breakpoints and their immediate flanking regions. | [
2,
43,
4008,
5541,
19,
14825,
3979,
1922,
1920,
2330,
17,
3824,
9694,
3148,
2359,
1966,
43,
3936,
1927,
9589,
11444,
22862,
18,
43,
4252,
5541,
19,
14825,
14154,
1927,
1920,
8017,
3148,
2359,
1982,
8117,
1922,
43,
24016,
2774,
1956,
9589,
11444,
22862,
12,
11912,
13,
18,
3244,
2333,
1927,
1920,
8336,
5465,
3404,
1925,
7413,
1927,
24,
9519,
1922,
7049,
2513,
16,
4189,
2007,
43,
4252,
5541,
1930,
7413,
4817,
15325,
43,
2590,
17,
4149,
5367,
1927,
1920,
2791,
7049,
2513,
3244,
1927,
1920,
8017,
3148,
2359,
2007,
43,
2752,
17,
4149,
9064,
1927,
2814,
3244,
2019,
1920,
5541,
24698,
18,
1920,
9103,
3244,
1982,
6119,
1942,
1920,
2791,
7049,
29,
3244,
1927,
1920,
8017,
3148,
2359,
2037,
5891,
16895,
1015,
1942,
5891,
19943,
1009,
9103,
1922,
1925,
12344,
7148,
18,
2052,
7374,
5092,
43,
8414,
21848,
2256,
3835,
2687,
24576,
12,
10646,
13,
1930,
5029,
1942,
43,
9839,
12462,
8905,
2019,
3835,
2687,
3507,
4522,
1025,
18,
2333,
1927,
5267,
13335,
17,
3343,
4461,
2037,
2698,
3146,
5210,
2037,
4789,
7001,
3404,
2444,
6247,
7905,
2007,
1920,
2791,
5465,
18,
2052,
2849,
1982,
3499,
1956,
1920,
3028,
3183,
2455,
1927,
1920,
8017,
3148,
2435,
1922,
1920,
7001,
1927,
1920,
2774,
1942,
2428,
2941,
2254,
2761,
9,
1927,
2690,
1922,
2791,
2094,
18,
1922,
4180,
16,
2038,
2162,
2899,
43,
2796,
1930,
30126,
13497,
11568,
2601,
1927,
14154,
1927,
1920,
2616,
8017,
3148,
2359,
18,
1920,
8162,
2856,
1927,
2052,
3979,
12,
10176,
1966,
11912,
17,
13149,
24605,
14174,
24895,
1033,
13,
4497,
24245,
16,
2876,
2176,
2278,
8156,
2796,
5881,
3337,
2007,
2835,
1927,
8862,
3709,
2481,
1922,
1920,
3979,
23800,
1930,
2310,
8426,
12679,
3451,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1346482 | [
"Isolation",
"and",
"characterization",
"of",
"new",
"highly",
"polymorphic",
"DNA",
"markers",
"from",
"the",
"Huntington",
"disease",
"region.",
"The",
"defect",
"causing",
"Huntington",
"disease",
"(HD)",
"has",
"been",
"mapped",
"to",
"4p16.3,",
"distal",
"to",
"the",
"DNA",
"marker",
"D4S10.",
"Subsequently,",
"additional",
"polymorphic",
"markers",
"closer",
"to",
"the",
"HD",
"gene",
"have",
"been",
"isolated,",
"which",
"has",
"led",
"to",
"the",
"establishment",
"of",
"predictive",
"testing",
"programs",
"for",
"individuals",
"at",
"risk",
"for",
"HD.",
"Approximately",
"17%",
"of",
"persons",
"presenting",
"to",
"the",
"Canadian",
"collaborative",
"study",
"for",
"predictive",
"testing",
"for",
"HD",
"have",
"not",
"received",
"any",
"modification",
"of",
"risk,",
"in",
"part",
"because",
"of",
"limited",
"informativeness",
"of",
"currently",
"available",
"DNA",
"markers.",
"Therefore,",
"more",
"highly",
"polymorphic",
"DNA",
"markers",
"are",
"needed,",
"which",
"will",
"further",
"increase",
"the",
"accuracy",
"and",
"availability",
"of",
"predictive",
"testing,",
"specifically",
"for",
"families",
"with",
"complex",
"or",
"incomplete",
"pedigree",
"structures.",
"In",
"addition,",
"new",
"markers",
"are",
"urgently",
"needed",
"in",
"order",
"to",
"refine",
"the",
"breakpoints",
"in",
"the",
"few",
"known",
"recombinant",
"HD",
"chromosomes,",
"which",
"could",
"allow",
"a",
"more",
"accurate",
"localization",
"of",
"the",
"HD",
"gene",
"within",
"4p16.3",
"and,",
"therefore,",
"accelerate",
"the",
"cloning",
"of",
"the",
"disease",
"gene.",
"In",
"this",
"study",
"we",
"present",
"the",
"identification",
"and",
"characterization",
"of",
"nine",
"new",
"polymorphic",
"DNA",
"markers,",
"including",
"three",
"markers",
"which",
"detect",
"highly",
"informative",
"multiallelic",
"VNTR-like",
"polymorphisms",
"with",
"PIC",
"values",
"of",
"up",
"to",
".84.",
"These",
"markers",
"have",
"been",
"isolated",
"from",
"a",
"cloned",
"region",
"of",
"DNA",
"which",
"has",
"been",
"previously",
"mapped",
"approximately",
"1,000",
"kb",
"from",
"the",
"4p",
"telomere."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Isolation and characterization of new highly polymorphic DNA markers from the Huntington disease region. The defect causing Huntington disease (HD) has been mapped to 4p16.3, distal to the DNA marker D4S10. Subsequently, additional polymorphic markers closer to the HD gene have been isolated, which has led to the establishment of predictive testing programs for individuals at risk for HD. Approximately 17% of persons presenting to the Canadian collaborative study for predictive testing for HD have not received any modification of risk, in part because of limited informativeness of currently available DNA markers. Therefore, more highly polymorphic DNA markers are needed, which will further increase the accuracy and availability of predictive testing, specifically for families with complex or incomplete pedigree structures. In addition, new markers are urgently needed in order to refine the breakpoints in the few known recombinant HD chromosomes, which could allow a more accurate localization of the HD gene within 4p16.3 and, therefore, accelerate the cloning of the disease gene. In this study we present the identification and characterization of nine new polymorphic DNA markers, including three markers which detect highly informative multiallelic VNTR-like polymorphisms with PIC values of up to .84. These markers have been isolated from a cloned region of DNA which has been previously mapped approximately 1,000 kb from the 4p telomere. | [
2,
7152,
1930,
7285,
1927,
2814,
3626,
14240,
2678,
4432,
2037,
1920,
24289,
2573,
3031,
18,
1920,
7374,
7538,
24289,
2573,
12,
4515,
13,
2258,
2252,
9225,
1942,
24,
5113,
1016,
18,
23,
16,
6583,
1942,
1920,
2678,
4966,
16603,
12030,
1008,
18,
5326,
16,
3281,
14240,
4432,
11468,
1942,
1920,
4515,
2359,
2162,
2252,
3937,
16,
2154,
2258,
4866,
1942,
1920,
11108,
1927,
6207,
4213,
6144,
1958,
3445,
2019,
2565,
1958,
4515,
18,
3993,
2752,
9,
1927,
7618,
8326,
1942,
1920,
13870,
13961,
2161,
1958,
6207,
4213,
1958,
4515,
2162,
2084,
4004,
2967,
6295,
1927,
2565,
16,
1922,
3131,
2882,
1927,
3892,
12840,
2971,
1927,
5077,
3322,
2678,
4432,
18,
2955,
16,
2253,
3626,
14240,
2678,
4432,
2032,
4500,
16,
2154,
2832,
2520,
2760,
1920,
4923,
1930,
6855,
1927,
6207,
4213,
16,
4475,
1958,
5767,
1956,
2796,
2014,
9876,
22336,
4061,
18,
1922,
2459,
16,
2814,
4432,
2032,
23749,
4500,
1922,
3238,
1942,
21044,
1920,
23800,
1922,
1920,
3855,
3171,
5752,
4515,
8597,
16,
2154,
2578,
3235,
43,
2253,
6305,
5363,
1927,
1920,
4515,
2359,
2651,
24,
5113,
1016,
18,
23,
1930,
16,
2955,
16,
15947,
1920,
11501,
1927,
1920,
2573,
2359,
18,
1922,
2052,
2161,
2038,
2481,
1920,
4824,
1930,
7285,
1927,
6360,
2814,
14240,
2678,
4432,
16,
2710,
2559,
4432,
2154,
4277,
3626,
12840,
2779,
5915,
1935,
18155,
1997,
17,
3189,
8321,
1956,
7271,
2851,
1927,
2353,
1942,
18,
5686,
18,
2144,
4432,
2162,
2252,
3937,
2037,
43,
8283,
3031,
1927,
2678,
2154,
2258,
2252,
3024,
9225,
3993,
21,
16,
3240,
6633,
2037,
1920,
24,
1034,
12025,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
11078480 | [
"The",
"extent",
"of",
"linkage",
"disequilibrium",
"in",
"four",
"populations",
"with",
"distinct",
"demographic",
"histories.",
"The",
"design",
"and",
"feasibility",
"of",
"whole-genome-association",
"studies",
"are",
"critically",
"dependent",
"on",
"the",
"extent",
"of",
"linkage",
"disequilibrium",
"(LD)",
"between",
"markers.",
"Although",
"there",
"has",
"been",
"extensive",
"theoretical",
"discussion",
"of",
"this,",
"few",
"empirical",
"data",
"exist.",
"The",
"authors",
"have",
"determined",
"the",
"extent",
"of",
"LD",
"among",
"38",
"biallelic",
"markers",
"with",
"minor",
"allele",
"frequencies",
">.1,",
"since",
"these",
"are",
"most",
"comparable",
"to",
"the",
"common",
"disease-susceptibility",
"polymorphisms",
"that",
"association",
"studies",
"aim",
"to",
"detect.",
"The",
"markers",
"come",
"from",
"three",
"chromosomal",
"regions-1,335",
"kb",
"on",
"chromosome",
"13q12-13,",
"380",
"kb",
"on",
"chromosome",
"19q13.2,",
"and",
"120",
"kb",
"on",
"chromosome",
"22q13.3-which",
"have",
"been",
"extensively",
"mapped.",
"These",
"markers",
"were",
"examined",
"in",
"approximately",
"1,600",
"individuals",
"from",
"four",
"populations,",
"all",
"of",
"European",
"origin",
"but",
"with",
"different",
"demographic",
"histories;",
"Afrikaners,",
"Ashkenazim,",
"Finns,",
"and",
"East",
"Anglian",
"British.",
"There",
"are",
"few",
"differences,",
"either",
"in",
"allele",
"frequencies",
"or",
"in",
"LD,",
"among",
"the",
"populations",
"studied.",
"A",
"similar",
"inverse",
"relationship",
"was",
"found",
"between",
"LD",
"and",
"distance",
"in",
"each",
"genomic",
"region",
"and",
"in",
"each",
"population.",
"Mean",
"D'",
"is.68",
"for",
"marker",
"pairs",
"<5",
"kb",
"apart",
"and",
"is.24",
"for",
"pairs",
"separated",
"by",
"10-20",
"kb,",
"and",
"the",
"level",
"of",
"LD",
"is",
"not",
"different",
"from",
"that",
"seen",
"in",
"unlinked",
"marker",
"pairs",
"separated",
"by",
">500",
"kb.",
"However,",
"only",
"50%",
"of",
"marker",
"pairs",
"at",
"distances",
"<5",
"kb",
"display",
"sufficient",
"LD",
"(delta>.3)",
"to",
"be",
"useful",
"in",
"association",
"studies.",
"Results",
"of",
"the",
"present",
"study,",
"if",
"representative",
"of",
"the",
"whole",
"genome,",
"suggest",
"that",
"a",
"whole-genome",
"scan",
"searching",
"for",
"common",
"disease-susceptibility",
"alleles",
"would",
"require",
"markers",
"spaced",
"<",
"or",
"=",
"5",
"kb",
"apart."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The extent of linkage disequilibrium in four populations with distinct demographic histories. The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart. | [
2,
1920,
5064,
1927,
8611,
19264,
1922,
3006,
4098,
1956,
4493,
6611,
17383,
18,
1920,
3036,
1930,
10067,
1927,
4292,
17,
3843,
17,
3279,
2351,
2032,
9790,
3100,
1990,
1920,
5064,
1927,
8611,
19264,
12,
5091,
13,
2192,
4432,
18,
2876,
2276,
2258,
2252,
6475,
7768,
7248,
1927,
2052,
16,
3855,
9203,
2230,
5516,
18,
1920,
3875,
2162,
3180,
1920,
5064,
1927,
5091,
2706,
3738,
27888,
1952,
3742,
4432,
1956,
5857,
5465,
6458,
34,
18,
21,
16,
3328,
2144,
2032,
2501,
5596,
1942,
1920,
3059,
2573,
17,
6461,
8321,
1988,
3279,
2351,
3774,
1942,
4277,
18,
1920,
4432,
10449,
2037,
2559,
9220,
3451,
17,
21,
16,
23106,
6633,
1990,
5597,
2590,
16886,
1028,
17,
2590,
16,
19275,
6633,
1990,
5597,
2282,
16886,
1010,
18,
22,
16,
1930,
6103,
6633,
1990,
5597,
2950,
16886,
1010,
18,
23,
17,
2154,
2162,
2252,
9172,
9225,
18,
2144,
4432,
1985,
3572,
1922,
3993,
21,
16,
8333,
3445,
2037,
3006,
4098,
16,
2136,
1927,
6785,
4853,
2308,
1956,
2413,
6611,
17383,
31,
2221,
3027,
7640,
5781,
16,
13696,
11341,
3408,
1980,
16,
3502,
3355,
16,
1930,
10319,
3409,
12191,
1928,
14885,
18,
2276,
2032,
3855,
2886,
16,
3108,
1922,
5465,
6458,
2014,
1922,
5091,
16,
2706,
1920,
4098,
3942,
18,
43,
2551,
9526,
3303,
1982,
2435,
2192,
5091,
1930,
4819,
1922,
2362,
4935,
3031,
1930,
1922,
2362,
2973,
18,
2667,
46,
11,
1977,
18,
5117,
1958,
4966,
5803,
32,
25,
6633,
9615,
1930,
1977,
18,
2686,
1958,
5803,
6239,
2007,
2119,
17,
2036,
6633,
16,
1930,
1920,
2237,
1927,
5091,
1977,
2084,
2413,
2037,
1988,
3945,
1922,
4774,
2839,
1919,
4966,
5803,
6239,
2007,
34,
4599,
6633,
18,
2406,
16,
2444,
2761,
9,
1927,
4966,
5803,
2019,
9104,
32,
25,
6633,
4434,
5409,
5091,
12,
9649,
34,
18,
23,
13,
1942,
1998,
4707,
1922,
3279,
2351,
18,
2274,
1927,
1920,
2481,
2161,
16,
2647,
5051,
1927,
1920,
4292,
3843,
16,
3220,
1988,
43,
4292,
17,
3843,
4519,
14447,
1958,
3059,
2573,
17,
6461,
7096,
2962,
4350,
4432,
19303,
32,
2014,
33,
25,
6633,
9615,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
17999356 | [
"Genetic",
"basis",
"for",
"correction",
"of",
"very-long-chain",
"acyl-coenzyme",
"A",
"dehydrogenase",
"deficiency",
"by",
"bezafibrate",
"in",
"patient",
"fibroblasts:",
"toward",
"a",
"genotype-based",
"therapy.",
"Very-long-chain",
"acyl-coenzyme",
"A",
"dehydrogenase",
" ",
"(",
"VLCAD",
")",
"deficiency",
"is",
"an",
"inborn",
"mitochondrial",
"fatty-acid",
"beta-oxidation",
"(FAO)",
"defect",
"associated",
"with",
"a",
"broad",
"mutational",
"spectrum,",
"with",
"phenotypes",
"ranging",
"from",
"fatal",
"cardiopathy",
"in",
"infancy",
"to",
"adolescent-onset",
"myopathy,",
"and",
"for",
"which",
"there",
"is",
"no",
"established",
"treatment.",
"Recent",
"data",
"suggest",
"that",
"bezafibrate",
"could",
"improve",
"the",
"FAO",
"capacities",
"in",
"beta-oxidation-deficient",
"cells,",
"by",
"enhancing",
"the",
"residual",
"level",
"of",
"mutant",
"enzyme",
"activity",
"via",
"gene-expression",
"stimulation.",
"Since",
"VLCAD-deficient",
"patients",
"frequently",
"harbor",
"missense",
"mutations",
"with",
"unpredictable",
"effects",
"on",
"enzyme",
"activity,",
"we",
"investigated",
"the",
"response",
"to",
"bezafibrate",
"as",
"a",
"function",
"of",
"genotype",
"in",
"33",
"VLCAD-deficient",
"fibroblasts",
"representing",
"45",
"different",
"mutations.",
"Treatment",
"with",
"bezafibrate",
"(400",
"microM",
"for",
"48",
"h)",
"resulted",
"in",
"a",
"marked",
"increase",
"in",
"FAO",
"capacities,",
"often",
"leading",
"to",
"restoration",
"of",
"normal",
"values,",
"for",
"21",
"genotypes",
"that",
"mainly",
"corresponded",
"to",
"patients",
"with",
"the",
"myopathic",
"phenotype.",
"In",
"contrast,",
"bezafibrate",
"induced",
"no",
"changes",
"in",
"FAO",
"for",
"11",
"genotypes",
"corresponding",
"to",
"severe",
"neonatal",
"or",
"infantile",
"phenotypes.",
"This",
"pattern",
"of",
"response",
"was",
"not",
"due",
"to",
"differential",
"inductions",
"of",
"VLCAD",
"messenger",
"RNA,",
"as",
"shown",
"by",
"quantitative",
"real-time",
"polymerase",
"chain",
"reaction,",
"but",
"reflected",
"variable",
"increases",
"in",
"measured",
"VLCAD",
" ",
"residual",
"enzyme",
"activity",
"in",
"response",
"to",
"bezafibrate.",
"Genotype",
"cross-analysis",
"allowed",
"the",
"identification",
"of",
"alleles",
"carrying",
"missense",
"mutations,",
"which",
"could",
"account",
"for",
"these",
"different",
"pharmacological",
"profiles",
"and,",
"on",
"this",
"basis,",
"led",
"to",
"the",
"characterization",
"of",
"9",
"mild",
"and",
"11",
"severe",
"missense",
"mutations.",
"Altogether,",
"the",
"responses",
"to",
"bezafibrate",
"reflected",
"the",
"severity",
"of",
"the",
"metabolic",
"blockage",
"in",
"various",
"genotypes,",
"which",
"appeared",
"to",
"be",
"correlated",
"with",
"the",
"phenotype,",
"thus",
"providing",
"a",
"new",
"approach",
"for",
"analysis",
"of",
"genetic",
"heterogeneity.",
"Finally,",
"this",
"study",
"emphasizes",
"the",
"potential",
"of",
"bezafibrate,",
"a",
"widely",
"prescribed",
"hypolipidemic",
"drug,",
"for",
"the",
"correction",
"of",
"VLCAD",
"VLCAD",
" ",
"messenger",
"RNA,",
"as",
"shown",
"by",
"quantitative",
"real-time",
"polymerase",
"chain",
"reaction,",
"but",
"reflected",
"variable",
"increases",
"in",
"measured",
"VLCAD",
"residual",
"enzyme",
"activity",
"in",
"response",
"to",
"bezafibrate.",
"Genotype",
"cross-analysis",
"allowed",
"the",
"identification",
"of",
"alleles",
"carrying",
"missense",
"mutations,",
"which",
"could",
"account",
"for",
"these",
"different",
"pharmacological",
"profiles",
"and,",
"on",
"this",
"basis,",
"led",
"to",
"the",
"characterization",
"of",
"9",
"mild",
"and",
"11",
"severe",
"missense",
"mutations.",
"Altogether,",
"the",
"responses",
"to",
"bezafibrate",
"reflected",
"the",
"severity",
"of",
"the",
"metabolic",
"blockage",
"in",
"various",
"genotypes,",
"which",
"appeared",
"to",
"be",
"correlated",
"with",
"the",
"phenotype,",
"thus",
"providing",
"a",
"new",
"approach",
"for",
"analysis",
"of",
"genetic",
"heterogeneity.",
"Finally,",
"this",
"study",
"emphasizes",
"the",
"potential",
"of",
"bezafibrate,",
"a",
"widely",
"prescribed",
"hypolipidemic",
"drug,",
"for",
"the",
"correction",
"of",
"VLCAD",
"deficiency",
"and",
"exemplifies",
"the",
"integration",
"of",
"molecular",
"information",
"in",
"a",
"therapeutic",
"strategy."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Very-long-chain acyl-coenzyme A dehydrogenase ( VLCAD ) deficiency is an inborn mitochondrial fatty-acid beta-oxidation (FAO) defect associated with a broad mutational spectrum, with phenotypes ranging from fatal cardiopathy in infancy to adolescent-onset myopathy, and for which there is no established treatment. Recent data suggest that bezafibrate could improve the FAO capacities in beta-oxidation-deficient cells, by enhancing the residual level of mutant enzyme activity via gene-expression stimulation. Since VLCAD-deficient patients frequently harbor missense mutations with unpredictable effects on enzyme activity, we investigated the response to bezafibrate as a function of genotype in 33 VLCAD-deficient fibroblasts representing 45 different mutations. Treatment with bezafibrate (400 microM for 48 h) resulted in a marked increase in FAO capacities, often leading to restoration of normal values, for 21 genotypes that mainly corresponded to patients with the myopathic phenotype. In contrast, bezafibrate induced no changes in FAO for 11 genotypes corresponding to severe neonatal or infantile phenotypes. This pattern of response was not due to differential inductions of VLCAD messenger RNA, as shown by quantitative real-time polymerase chain reaction, but reflected variable increases in measured VLCAD residual enzyme activity in response to bezafibrate. Genotype cross-analysis allowed the identification of alleles carrying missense mutations, which could account for these different pharmacological profiles and, on this basis, led to the characterization of 9 mild and 11 severe missense mutations. Altogether, the responses to bezafibrate reflected the severity of the metabolic blockage in various genotypes, which appeared to be correlated with the phenotype, thus providing a new approach for analysis of genetic heterogeneity. Finally, this study emphasizes the potential of bezafibrate, a widely prescribed hypolipidemic drug, for the correction of VLCAD VLCAD messenger RNA, as shown by quantitative real-time polymerase chain reaction, but reflected variable increases in measured VLCAD residual enzyme activity in response to bezafibrate. Genotype cross-analysis allowed the identification of alleles carrying missense mutations, which could account for these different pharmacological profiles and, on this basis, led to the characterization of 9 mild and 11 severe missense mutations. Altogether, the responses to bezafibrate reflected the severity of the metabolic blockage in various genotypes, which appeared to be correlated with the phenotype, thus providing a new approach for analysis of genetic heterogeneity. Finally, this study emphasizes the potential of bezafibrate, a widely prescribed hypolipidemic drug, for the correction of VLCAD deficiency and exemplifies the integration of molecular information in a therapeutic strategy. | [
2,
3299,
4859,
1958,
6820,
1927,
3345,
17,
2815,
17,
4659,
11337,
17,
22051,
43,
9294,
6179,
2007,
28861,
2624,
3693,
2010,
1922,
2774,
7001,
30,
4205,
43,
5619,
17,
2454,
3181,
18,
3345,
17,
2815,
17,
4659,
11337,
17,
22051,
43,
9294,
12,
9920,
3375,
1007,
13,
6179,
1977,
1925,
1922,
23419,
4596,
5934,
17,
2687,
4666,
17,
6638,
12,
28502,
13,
7374,
2458,
1956,
43,
4949,
13736,
5648,
16,
1956,
6568,
6485,
2037,
11990,
21129,
9112,
1012,
1922,
17591,
1942,
8402,
17,
4727,
25017,
16,
1930,
1958,
2154,
2276,
1977,
2239,
4379,
2311,
18,
3505,
2230,
3220,
1988,
28861,
2624,
3693,
2010,
2578,
3326,
1920,
28502,
16817,
1922,
4666,
17,
6638,
17,
5778,
2094,
16,
2007,
9221,
1920,
6615,
2237,
1927,
3606,
4113,
2455,
3454,
2359,
17,
2294,
4177,
18,
3328,
9920,
3375,
1007,
17,
5778,
2132,
5467,
14355,
13519,
3527,
1956,
22512,
2564,
1990,
4113,
2455,
16,
2038,
3845,
1920,
2644,
1942,
28861,
2624,
3693,
2010,
1966,
43,
2347,
1927,
5619,
1922,
3401,
9920,
3375,
1007,
17,
5778,
7001,
7479,
3607,
2413,
3527,
18,
2311,
1956,
28861,
2624,
3693,
2010,
12,
5805,
7709,
1958,
3427,
50,
13,
4306,
1922,
43,
4961,
2760,
1922,
28502,
16817,
16,
3868,
4523,
1942,
12010,
1927,
2791,
2851,
16,
1958,
2900,
7059,
1988,
4994,
13274,
1942,
2132,
1956,
1920,
15924,
9112,
1935,
4629,
18,
1922,
3320,
16,
28861,
2624,
3693,
2010,
2719,
2239,
2840,
1922,
28502,
1958,
2513,
7059,
3980,
1942,
4010,
7985,
2014,
26975,
6568,
18,
2052,
3114,
1927,
2644,
1982,
2084,
2810,
1942,
5611,
4408,
1036,
1927,
9920,
3375,
1007,
16716,
3146,
16,
1966,
2522,
2007,
4794,
4105,
17,
2367,
6479,
4659,
3227,
16,
2308,
8830,
4650,
4041,
1922,
3045,
9920,
3375,
1007,
6615,
4113,
2455,
1922,
2644,
1942,
28861,
2624,
3693,
2010,
18,
5619,
3567,
17,
2333,
5563,
1920,
4824,
1927,
7096,
8215,
13519,
3527,
16,
2154,
2578,
5042,
1958,
2144,
2413,
7683,
5554,
1930,
16,
1990,
2052,
4859,
16,
4866,
1942,
1920,
7285,
1927,
29,
5809,
1930,
2513,
4010,
13519,
3527,
18,
14072,
16,
1920,
3387,
1942,
28861,
2624,
3693,
2010,
8830,
1920,
5155,
1927,
1920,
4487,
23615,
1922,
3425,
7059,
16,
2154,
6209,
1942,
1998,
4374,
1956,
1920,
4629,
16,
2842,
5453,
43,
2814,
2998,
1958,
2333,
1927,
3299,
6808,
18,
4342,
16,
2052,
2161,
19442,
1920,
2889,
1927,
28861,
2624,
3693,
2010,
16,
43,
5673,
9975,
14395,
8257,
2261,
4913,
2838,
16,
1958,
1920,
6820,
1927,
9920,
3375,
1007,
9920,
3375,
1007,
16716,
3146,
16,
1966,
2522,
2007,
4794,
4105,
17,
2367,
6479,
4659,
3227,
16,
2308,
8830,
4650,
4041,
1922,
3045,
9920,
3375,
1007,
6615,
4113,
2455,
1922,
2644,
1942,
28861,
2624,
3693,
2010,
18,
5619,
3567,
17,
2333,
5563,
1920,
4824,
1927,
7096,
8215,
13519,
3527,
16,
2154,
2578,
5042,
1958,
2144,
2413,
7683,
5554,
1930,
16,
1990,
2052,
4859,
16,
4866,
1942,
1920,
7285,
1927,
29,
5809,
1930,
2513,
4010,
13519,
3527,
18,
14072,
16,
1920,
3387,
1942,
28861,
2624,
3693,
2010,
8830,
1920,
5155,
1927,
1920,
4487,
23615,
1922,
3425,
7059,
16,
2154,
6209,
1942,
1998,
4374,
1956,
1920,
4629,
16,
2842,
5453,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20970104 | [
"Mutations",
"in",
"NEXN",
",",
"a",
"Z-disc",
"gene,",
"are",
"associated",
"with",
"hypertrophic",
"cardiomyopathy.",
"Hypertrophic",
"cardiomyopathy",
"(HCM),",
"the",
"most",
"common",
"inherited",
"cardiac",
"disorder,",
"is",
"characterized",
"by",
"increased",
"ventricular",
"wall",
"thickness",
"that",
"cannot",
"be",
"explained",
"by",
"underlying",
"conditions,",
"cadiomyocyte",
"hypertrophy",
"and",
"disarray,",
"and",
"increased",
"myocardial",
"fibrosis.",
"In",
"as",
"many",
"as",
"50%",
"of",
"HCM",
"cases,",
"the",
"genetic",
"cause",
"remains",
"unknown,",
"suggesting",
"that",
"more",
"genes",
"may",
"be",
"involved.",
"Nexilin,",
"encoded",
"by",
"NEXN",
",",
"is",
"a",
"cardiac",
"Z-disc",
"protein",
"recently",
"identified",
"as",
"a",
"crucial",
"protein",
"that",
"functions",
"to",
"protect",
"cardiac",
"Z-discs",
"from",
"forces",
"generated",
"within",
"the",
"sarcomere.",
"We",
"screened",
"NEXN",
" ",
"in",
"121",
"unrelated",
"HCM",
"patients",
"who",
"did",
"not",
"carry",
"any",
"mutation",
"in",
"eight",
"genes",
"commonly",
"mutated",
"in",
"myofilament",
"disease.",
"Two",
"missense",
"mutations,",
"c.391C>G",
" ",
"(",
"p.Q131E",
")",
"and",
"c.835C>T",
" ",
"(",
"p.R279C",
"),",
"were",
"identified",
"in",
"exons",
"5",
"and",
"8",
"of",
"NEXN",
",",
"respectively,",
"in",
"two",
"probands.",
"Each",
"of",
"the",
"two",
"mutations",
"segregated",
"with",
"the",
"HCM",
"phenotype",
"in",
"the",
"family",
"and",
"was",
"absent",
"in",
"384",
"control",
"chromosomes.",
"In",
"silico",
"analysis",
"revealed",
"that",
"both",
"of",
"the",
"mutations",
"affect",
"highly",
"conserved",
"amino",
"acid",
"residues,",
"which",
"are",
"predicted",
"to",
"be",
"functionally",
"deleterious.",
"Cellular",
"transfection",
"studies",
"showed",
"that",
"the",
"two",
"mutations",
"resulted",
"in",
"local",
"accumulations",
"of",
"nexilin",
"and",
"that",
"the",
"expressed",
"fragment",
"of",
"actin-binding",
"domain",
"containing",
"p.Q131E",
" ",
"completely",
"lost",
"the",
"ability",
"to",
"bind",
"F-actin",
"in",
"C2C12",
"cells.",
"Coimmunoprecipitation",
"assay",
"indicated",
"that",
"the",
"p.Q131E",
" ",
"mutation",
"decreased",
"the",
"binding",
"of",
"full-length",
"NEXN",
" ",
"to",
"α-actin",
"and",
"abolished",
"the",
"interaction",
"between",
"the",
"fragment",
"of",
"actin-binding",
"domain",
"and",
"α-actin.",
"Therefore,",
"the",
"mutations",
"in",
"NEXN",
" ",
"that",
"we",
"describe",
"here",
"may",
"further",
"expand",
"the",
"knowledge",
"of",
"Z-disc",
"genes",
"in",
"the",
"pathogenesis",
"of",
"HCM."
] | [
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Mutations in NEXN , a Z-disc gene, are associated with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is characterized by increased ventricular wall thickness that cannot be explained by underlying conditions, cadiomyocyte hypertrophy and disarray, and increased myocardial fibrosis. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that more genes may be involved. Nexilin, encoded by NEXN , is a cardiac Z-disc protein recently identified as a crucial protein that functions to protect cardiac Z-discs from forces generated within the sarcomere. We screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease. Two missense mutations, c.391C>G ( p.Q131E ) and c.835C>T ( p.R279C ), were identified in exons 5 and 8 of NEXN , respectively, in two probands. Each of the two mutations segregated with the HCM phenotype in the family and was absent in 384 control chromosomes. In silico analysis revealed that both of the mutations affect highly conserved amino acid residues, which are predicted to be functionally deleterious. Cellular transfection studies showed that the two mutations resulted in local accumulations of nexilin and that the expressed fragment of actin-binding domain containing p.Q131E completely lost the ability to bind F-actin in C2C12 cells. Coimmunoprecipitation assay indicated that the p.Q131E mutation decreased the binding of full-length NEXN to α-actin and abolished the interaction between the fragment of actin-binding domain and α-actin. Therefore, the mutations in NEXN that we describe here may further expand the knowledge of Z-disc genes in the pathogenesis of HCM. | [
2,
3527,
1922,
24079,
1022,
16,
43,
68,
17,
2863,
2359,
16,
2032,
2458,
1956,
17437,
14141,
18,
17437,
14141,
12,
21923,
13,
16,
1920,
2501,
3059,
12911,
4435,
4770,
16,
1977,
4378,
2007,
2502,
6493,
4821,
5769,
1988,
5156,
1998,
6094,
2007,
5030,
2961,
16,
5643,
3940,
14930,
4463,
11014,
1930,
2054,
26753,
16,
1930,
2502,
6497,
6769,
18,
1922,
1966,
3086,
1966,
2761,
9,
1927,
21923,
2919,
16,
1920,
3299,
3936,
4497,
5435,
16,
3783,
1988,
2253,
2628,
2278,
1998,
3286,
18,
24079,
16207,
16,
7905,
2007,
24079,
1022,
16,
1977,
43,
4435,
68,
17,
2863,
2213,
3998,
2899,
1966,
43,
6608,
2213,
1988,
4088,
1942,
9145,
4435,
68,
17,
16380,
2037,
9146,
3999,
2651,
1920,
30164,
18,
2038,
8582,
24079,
1022,
1922,
11844,
10295,
21923,
2132,
2746,
2811,
2084,
9875,
2967,
3979,
1922,
5066,
2628,
5384,
8336,
1922,
15924,
27904,
2573,
18,
2288,
13519,
3527,
16,
45,
18,
29567,
1030,
34,
49,
12,
58,
18,
22027,
6800,
1021,
13,
1930,
45,
18,
5893,
20118,
34,
62,
12,
58,
18,
7261,
9364,
1030,
13,
16,
1985,
2899,
1922,
10419,
25,
1930,
28,
1927,
24079,
1022,
16,
2763,
16,
1922,
2288,
23259,
18,
2362,
1927,
1920,
2288,
3527,
22439,
1956,
1920,
21923,
4629,
1922,
1920,
3416,
1930,
1982,
7685,
1922,
19412,
2285,
8597,
18,
1922,
14270,
2333,
3404,
1988,
2321,
1927,
1920,
3527,
4081,
3626,
5305,
3835,
2687,
4248,
16,
2154,
2032,
4396,
1942,
1998,
9346,
12524,
18,
3689,
6496,
2351,
2594,
1988,
1920,
2288,
3527,
4306,
1922,
3076,
4858,
1036,
1927,
24079,
16207,
1930,
1988,
1920,
3198,
5302,
1927,
4718,
17,
2743,
3418,
3165,
58,
18,
22027,
6800,
1021,
5796,
7621,
1920,
3682,
1942,
4566,
48,
17,
4718,
1922,
21467,
2094,
18,
23468,
7194,
3381,
3391,
1988,
1920,
58,
18,
22027,
6800,
1021,
3979,
3261,
1920,
2743,
1927,
4125,
17,
3471,
24079,
1022,
1942,
160,
17,
4718,
1930,
10979,
1920,
2835,
2192,
1920,
5302,
1927,
4718,
17,
2743,
3418,
1930,
160,
17,
4718,
18,
2955,
16,
1920,
3527,
1922,
24079,
1022,
1988,
2038,
5993,
3410,
2278,
2520,
7305,
1920,
4163,
1927,
68,
17,
2863,
2628,
1922,
1920,
6559,
1927,
21923,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
0,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
15611928 | [
"Fine",
"mapping",
"and",
"positional",
"candidate",
"studies",
"identify",
"HLA-G",
" ",
"as",
"an",
"asthma",
"susceptibility",
"gene",
"on",
"chromosome",
"6p21.",
"Asthma",
"affects",
"nearly",
"14",
"million",
"people",
"worldwide",
"and",
"has",
"been",
"steadily",
"increasing",
"in",
"frequency",
"for",
"the",
"past",
"50",
"years.",
"Although",
"environmental",
"factors",
"clearly",
"influence",
"the",
"onset,",
"progression,",
"and",
"severity",
"of",
"this",
"disease,",
"family",
"and",
"twin",
"studies",
"indicate",
"that",
"genetic",
"variation",
"also",
"influences",
"susceptibility.",
"Linkage",
"of",
"asthma",
"and",
"related",
"phenotypes",
"to",
"chromosome",
"6p21",
"has",
"been",
"reported",
"in",
"seven",
"genome",
"screens,",
"making",
"it",
"the",
"most",
"replicated",
"region",
"of",
"the",
"genome.",
"However,",
"because",
"many",
"genes",
"with",
"individually",
"small",
"effects",
"are",
"likely",
"to",
"contribute",
"to",
"risk,",
"identification",
"of",
"asthma",
"susceptibility",
"loci",
"has",
"been",
"challenging.",
"In",
"this",
"study,",
"we",
"present",
"evidence",
"from",
"four",
"independent",
"samples",
"in",
"support",
"of",
"HLA-G",
" ",
"as",
"a",
"novel",
"asthma",
"and",
"bronchial",
"hyperresponsiveness",
"susceptibility",
"gene",
"in",
"the",
"human",
"leukocyte",
"antigen",
"region",
"on",
"chromosome",
"6p21,",
"and",
"we",
"speculate",
"that",
"this",
"gene",
"might",
"contribute",
"to",
"risk",
"for",
"other",
"inflammatory",
"diseases",
"that",
"show",
"linkage",
"to",
"this",
"region."
] | [
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region. | [
2,
8882,
7084,
1930,
20172,
6610,
2351,
3512,
7225,
17,
49,
1966,
1925,
6678,
6461,
2359,
1990,
5597,
26,
5991,
1009,
18,
6678,
6886,
6737,
2607,
7068,
4329,
8563,
1930,
2258,
2252,
21283,
3605,
1922,
3528,
1958,
1920,
5375,
2761,
2739,
18,
2876,
4813,
2790,
5436,
4039,
1920,
4727,
16,
4380,
16,
1930,
5155,
1927,
2052,
2573,
16,
3416,
1930,
13392,
2351,
3579,
1988,
3299,
4516,
2222,
8061,
6461,
18,
8611,
1927,
6678,
1930,
2712,
6568,
1942,
5597,
26,
5991,
1009,
2258,
2252,
2568,
1922,
5260,
3843,
15007,
16,
5399,
2176,
1920,
2501,
13169,
3031,
1927,
1920,
3843,
18,
2406,
16,
2882,
3086,
2628,
1956,
9864,
2858,
2564,
2032,
3205,
1942,
4672,
1942,
2565,
16,
4824,
1927,
6678,
6461,
6971,
2258,
2252,
8764,
18,
1922,
2052,
2161,
16,
2038,
2481,
3095,
2037,
3006,
3484,
2785,
1922,
3373,
1927,
7225,
17,
49,
1966,
43,
4008,
6678,
1930,
14700,
4194,
17552,
7838,
6461,
2359,
1922,
1920,
2616,
11864,
4730,
3031,
1990,
5597,
26,
5991,
1009,
16,
1930,
2038,
12322,
1988,
2052,
2359,
3284,
4672,
1942,
2565,
1958,
2303,
3769,
3902,
1988,
2146,
8611,
1942,
2052,
3031,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
18179886 | [
"Oncostatin",
"M",
"receptor-beta",
"mutations",
"underlie",
"familial",
"primary",
"localized",
"cutaneous",
"amyloidosis.",
"Familial",
"primary",
"localized",
"cutaneous",
"amyloidosis",
"(FPLCA)",
"is",
"an",
"autosomal-dominant",
"disorder",
"associated",
"with",
"chronic",
"skin",
"itching",
"and",
"deposition",
"of",
"epidermal",
"keratin",
"filament-associated",
"amyloid",
"material",
"in",
"the",
"dermis.",
"FPLCA",
"has",
"been",
"mapped",
"to",
"5p13.1-q11.2,",
"and",
"by",
"candidate",
"gene",
"analysis,",
"we",
"identified",
"missense",
"mutations",
"in",
"the",
"OSMR",
" ",
"gene,",
"encoding",
"oncostatin",
"M-specific",
"receptor",
"beta",
" ",
"(",
"OSMRbeta",
"),",
"in",
"three",
"families.",
"OSMRbeta",
" ",
"is",
"a",
"component",
"of",
"the",
"oncostatin",
"M",
"(OSM)",
"type",
"II",
"receptor",
" ",
"and",
"the",
"interleukin",
"(IL)-31",
"receptor",
",",
"and",
"cultured",
"FPLCA",
"keratinocytes",
"showed",
"reduced",
"activation",
"of",
"Jak/STAT,",
"MAPK,",
"and",
"PI3K/Akt",
"pathways",
"after",
"OSM",
" ",
"or",
"IL-31",
" ",
"cytokine",
"stimulation.",
"The",
"pathogenic",
"amino",
"acid",
"substitutions",
"are",
"located",
"within",
"the",
"extracellular",
"fibronectin",
"type",
"III-like",
"(FNIII)",
"domains,",
"regions",
"critical",
"for",
"receptor",
"dimerization",
"and",
"function.",
"OSM",
" ",
"and",
"IL-31",
"Oncostatin",
"M",
"receptor-beta",
" ",
"mutations",
"underlie",
"familial",
"primary",
"localized",
"cutaneous",
"amyloidosis.",
"Familial",
"primary",
"localized",
"cutaneous",
"amyloidosis",
"(FPLCA)",
"is",
"an",
"autosomal-dominant",
"disorder",
"associated",
"with",
"chronic",
"skin",
"itching",
"and",
"deposition",
"of",
"epidermal",
"keratin",
"filament-associated",
"amyloid",
"material",
"in",
"the",
"dermis.",
"FPLCA",
"has",
"been",
"mapped",
"to",
"5p13.1-q11.2,",
"and",
"by",
"candidate",
"gene",
"analysis,",
"we",
"identified",
"missense",
"mutations",
"in",
"the",
"OSMR",
"gene,",
"encoding",
"oncostatin",
"M-specific",
"receptor",
"beta",
"(OSMRbeta),",
"in",
"three",
"families.",
"OSMRbeta",
"is",
"a",
"component",
"of",
"the",
"oncostatin",
"M",
"(OSM)",
"type",
"II",
"receptor",
"and",
"the",
"interleukin",
"(IL)-31",
"receptor,",
"and",
"cultured",
"FPLCA",
"keratinocytes",
"showed",
"reduced",
"activation",
"of",
"Jak/STAT,",
"MAPK,",
"and",
"PI3K/Akt",
"pathways",
"after",
"OSM",
"or",
"IL-31",
"cytokine",
"stimulation.",
"The",
"pathogenic",
"amino",
"acid",
"substitutions",
"are",
"located",
"within",
"the",
"extracellular",
"fibronectin",
"type",
"III-like",
"(FNIII)",
"domains,",
"regions",
"critical",
"for",
"receptor",
"dimerization",
"and",
"function.",
"OSM",
"and",
"IL-31",
"signaling",
"have",
"been",
"implicated",
"in",
"keratinocyte",
"cell",
"proliferation,",
"differentiation,",
"apoptosis,",
"and",
"inflammation,",
"but",
"our",
"OSMR",
"data",
"in",
"individuals",
"with",
"FPLCA",
"represent",
"the",
"first",
"human",
"germline",
"mutations",
"in",
"this",
"cytokine",
"receptor",
"complex",
"and",
"provide",
"new",
"insight",
"into",
"mechanisms",
"of",
"skin",
"itching."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
2,
2,
2,
0,
0,
1,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta ( OSMRbeta ), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor , and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching. | [
2,
5595,
13712,
55,
3148,
17,
4666,
3527,
14150,
11444,
3065,
6579,
11276,
23899,
18,
11444,
3065,
6579,
11276,
23899,
12,
8621,
8293,
1019,
13,
1977,
1925,
13027,
17,
6379,
4770,
2458,
1956,
3724,
4407,
20687,
1941,
1930,
7860,
1927,
9844,
9743,
10797,
17,
2458,
8186,
3485,
1922,
1920,
20201,
18,
8621,
8293,
1019,
2258,
2252,
9225,
1942,
10925,
3633,
18,
21,
17,
22027,
1009,
18,
22,
16,
1930,
2007,
6610,
2359,
2333,
16,
2038,
2899,
13519,
3527,
1922,
1920,
9405,
1005,
2359,
16,
5797,
5595,
13712,
55,
17,
2487,
3148,
4666,
12,
9405,
16007,
9215,
13,
16,
1922,
2559,
5767,
18,
9405,
16007,
9215,
1977,
43,
4594,
1927,
1920,
5595,
13712,
55,
12,
9405,
13,
2601,
2890,
3148,
1930,
1920,
9198,
12,
2614,
13,
17,
3470,
3148,
16,
1930,
4789,
8621,
8293,
1019,
13454,
2594,
3028,
2936,
1927,
10108,
19,
3156,
16,
7859,
16,
1930,
7734,
19,
5496,
3873,
2256,
9405,
2014,
2614,
17,
3470,
6137,
4177,
18,
1920,
8070,
3835,
2687,
10682,
2032,
4810,
2651,
1920,
5329,
12848,
2601,
4337,
17,
3189,
12,
9945,
10831,
13,
4682,
16,
3451,
4140,
1958,
3148,
13640,
1930,
2347,
18,
9405,
1930,
2614,
17,
3470,
5595,
13712,
55,
3148,
17,
4666,
3527,
14150,
11444,
3065,
6579,
11276,
23899,
18,
11444,
3065,
6579,
11276,
23899,
12,
8621,
8293,
1019,
13,
1977,
1925,
13027,
17,
6379,
4770,
2458,
1956,
3724,
4407,
20687,
1941,
1930,
7860,
1927,
9844,
9743,
10797,
17,
2458,
8186,
3485,
1922,
1920,
20201,
18,
8621,
8293,
1019,
2258,
2252,
9225,
1942,
10925,
3633,
18,
21,
17,
22027,
1009,
18,
22,
16,
1930,
2007,
6610,
2359,
2333,
16,
2038,
2899,
13519,
3527,
1922,
1920,
9405,
1005,
2359,
16,
5797,
5595,
13712,
55,
17,
2487,
3148,
4666,
12,
9405,
16007,
9215,
13,
16,
1922,
2559,
5767,
18,
9405,
16007,
9215,
1977,
43,
4594,
1927,
1920,
5595,
13712,
55,
12,
9405,
13,
2601,
2890,
3148,
1930,
1920,
9198,
12,
2614,
13,
17,
3470,
3148,
16,
1930,
4789,
8621,
8293,
1019,
13454,
2594,
3028,
2936,
1927,
10108,
19,
3156,
16,
7859,
16,
1930,
7734,
19,
5496,
3873,
2256,
9405,
2014,
2614,
17,
3470,
6137,
4177,
18,
1920,
8070,
3835,
2687,
10682,
2032,
4810,
2651,
1920,
5329,
12848,
2601,
4337,
17,
3189,
12,
9945,
10831,
13,
4682,
16,
3451,
4140,
1958,
3148,
13640,
1930,
2347,
18,
9405,
1930,
2614,
17,
3470,
3197,
2162,
2252,
6835,
1922,
21771,
2024,
4031,
16,
4155,
16,
4091,
16,
1930,
4531,
16,
2308,
2342,
9405,
1005,
2230,
1922,
3445,
1956,
8621,
8293,
1019,
3015,
1920,
2561,
2616,
12237,
3527,
1922,
2052,
6137,
3148,
2796,
1930,
3394,
2814,
8090,
2460,
3531,
1927,
4407,
20687,
1941,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
2,
0,
0,
1,
2,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
2,
2,
1,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8533759 | [
"Phenylketonuria",
"mutation",
"analysis",
"in",
"Northern",
"Ireland:",
"a",
"rapid",
"stepwise",
"approach.",
"We",
"present",
"a",
"multistep",
"approach",
"for",
"the",
"rapid",
"analysis",
"of",
"phenylketonuria",
"(PKU)",
"mutations.",
"In",
"the",
"first",
"step,",
"three",
"common",
"mutations",
"and",
"a",
"polymorphic",
"short",
"tandem",
"repeat",
"(STR)",
"system",
"are",
"rapidly",
"analyzed",
"with",
"a",
"fluorescent",
"multiplex",
"assay.",
"In",
"the",
"second",
"step,",
"minihaplotypes",
"combining",
"STR",
"and",
"VNTR",
"data",
"are",
"used",
"to",
"determine",
"rare",
"mutations",
"likely",
"to",
"be",
"present",
"in",
"an",
"investigated",
"patient,",
"which",
"are",
"then",
"confirmed",
"by",
"restriction",
"enzyme",
"analysis.",
"The",
"remaining",
"mutations",
"are",
"analyzed",
"with",
"denaturant",
"gradient-gel",
"electrophoresis",
"and",
"sequencing.",
"The",
"first",
"two",
"steps",
"together",
"identify",
"both",
"mutations",
"in",
"90%-95%",
"of",
"PKU",
"patients,",
"and",
"results",
"can",
"be",
"obtained",
"within",
"2",
"d.",
"We",
"have",
"investigated",
"121",
"Northern",
"Irish",
"families",
"with",
"hyperphenylalaninemia,",
"including",
"virtually",
"all",
"patients",
"born",
"since",
"1972,",
"and",
"have",
"found",
"34",
"different",
"mutations",
"on",
"241",
"of",
"the",
"242",
"mutant",
"alleles.",
"Three",
"mutations",
"(",
"R408W",
",",
"I65T",
",",
"and",
"F39L",
"PKU",
" ",
"patients,",
"and",
"results",
"can",
"be",
"obtained",
"within",
"2",
"d.",
"We",
"have",
"investigated",
"121",
"Northern",
"Irish",
"families",
"with",
"hyperphenylalaninemia,",
"including",
"virtually",
"all",
"patients",
"born",
"since",
"1972,",
"and",
"have",
"found",
"34",
"different",
"mutations",
"on",
"241",
"of",
"the",
"242",
"mutant",
"alleles.",
"Three",
"mutations",
"(R408W,",
"I65T,",
"and",
"F39L)",
"account",
"for",
"57.5%",
"of",
"mutations,",
"while",
"14",
"mutations",
"occur",
"with",
"a",
"frequency",
"of",
"1%-6%.",
"The",
"present",
"analysis",
"system",
"is",
"efficient",
"and",
"inexpensive",
"and",
"is",
"particularly",
"well",
"suited",
"to",
"routine",
"mutation",
"analysis",
"in",
"a",
"diagnostic",
"setting."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
0,
3,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach. We present a multistep approach for the rapid analysis of phenylketonuria (PKU) mutations. In the first step, three common mutations and a polymorphic short tandem repeat (STR) system are rapidly analyzed with a fluorescent multiplex assay. In the second step, minihaplotypes combining STR and VNTR data are used to determine rare mutations likely to be present in an investigated patient, which are then confirmed by restriction enzyme analysis. The remaining mutations are analyzed with denaturant gradient-gel electrophoresis and sequencing. The first two steps together identify both mutations in 90%-95% of PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations ( R408W , I65T , and F39L PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations (R408W, I65T, and F39L) account for 57.5% of mutations, while 14 mutations occur with a frequency of 1%-6%. The present analysis system is efficient and inexpensive and is particularly well suited to routine mutation analysis in a diagnostic setting. | [
2,
7971,
18540,
1916,
8754,
3979,
2333,
1922,
9250,
20416,
30,
43,
4052,
13846,
2998,
18,
2038,
2481,
43,
13564,
22329,
2998,
1958,
1920,
4052,
2333,
1927,
7971,
18540,
1916,
8754,
12,
4652,
1032,
13,
3527,
18,
1922,
1920,
2561,
3537,
16,
2559,
3059,
3527,
1930,
43,
14240,
3662,
10361,
6865,
12,
2114,
13,
2433,
2032,
6221,
3265,
1956,
43,
6265,
12710,
3381,
18,
1922,
1920,
2812,
3537,
16,
9696,
2722,
20949,
2085,
1918,
9138,
2114,
1930,
18155,
1997,
2230,
2032,
2251,
1942,
3415,
5844,
3527,
3205,
1942,
1998,
2481,
1922,
1925,
3845,
2774,
16,
2154,
2032,
2759,
3982,
2007,
7587,
4113,
2333,
18,
1920,
5719,
3527,
2032,
3265,
1956,
9704,
20028,
1031,
6494,
17,
4669,
8633,
1930,
4754,
18,
1920,
2561,
2288,
5983,
4084,
3512,
2321,
3527,
1922,
3865,
9,
17,
3002,
9,
1927,
4652,
1032,
2132,
16,
1930,
2274,
2112,
1998,
2926,
2651,
22,
46,
18,
2038,
2162,
3845,
11844,
9250,
17187,
1023,
5767,
1956,
4194,
17616,
2199,
15769,
6026,
16,
2710,
13224,
2136,
2132,
8813,
3328,
20652,
16,
1930,
2162,
2435,
3540,
2413,
3527,
1990,
21616,
1927,
1920,
21679,
3606,
7096,
18,
2559,
3527,
12,
23103,
13895,
1018,
16,
51,
5964,
1031,
16,
1930,
14499,
1026,
1024,
4652,
1032,
2132,
16,
1930,
2274,
2112,
1998,
2926,
2651,
22,
46,
18,
2038,
2162,
3845,
11844,
9250,
17187,
1023,
5767,
1956,
4194,
17616,
2199,
15769,
6026,
16,
2710,
13224,
2136,
2132,
8813,
3328,
20652,
16,
1930,
2162,
2435,
3540,
2413,
3527,
1990,
21616,
1927,
1920,
21679,
3606,
7096,
18,
2559,
3527,
12,
23103,
13895,
1018,
16,
51,
5964,
1031,
16,
1930,
14499,
1026,
1024,
13,
5042,
1958,
4786,
18,
25,
9,
1927,
3527,
16,
2679,
2607,
3527,
4704,
1956,
43,
3528,
1927,
21,
9,
17,
26,
9,
18,
1920,
2481,
2333,
2433,
1977,
5807,
1930,
20321,
1930,
1977,
4443,
2486,
15311,
1942,
7341,
3979,
2333,
1922,
43,
4785,
4308,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
3,
4,
4,
0,
0,
3,
4,
4,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
16909394 | [
"Mutations",
"in",
"the",
"CEP290",
" ",
"(",
"NPHP6",
")",
"gene",
"are",
"a",
"frequent",
"cause",
"of",
"Leber",
"congenital",
"amaurosis.",
"Leber",
"congenital",
"amaurosis",
"(LCA)",
"is",
"one",
"of",
"the",
"main",
"causes",
"of",
"childhood",
"blindness.",
"To",
"date,",
"mutations",
"in",
"eight",
"genes",
"have",
"been",
"described,",
"which",
"together",
"account",
"for",
"approximately",
"45%",
"of",
"LCA",
"cases.",
"We",
"localized",
"the",
"genetic",
"defect",
"in",
"a",
"consanguineous",
"LCA-affected",
"family",
"from",
"Quebec",
"and",
"identified",
"a",
"splice",
"defect",
"in",
"a",
"gene",
"encoding",
"a",
"centrosomal",
"protein",
"(",
"CEP290",
").",
"The",
"defect",
"is",
"caused",
"by",
"an",
"intronic",
"mutation",
"(",
"c.2991+1655A-->G",
")",
"that",
"creates",
"a",
"strong",
"splice-donor",
"site",
"and",
"inserts",
"a",
"cryptic",
"exon",
"in",
"the",
"CEP290",
" ",
"messenger",
"RNA.",
"This",
"mutation",
"was",
"detected",
"in",
"16",
"(21%)",
"of",
"76",
"unrelated",
"patients",
"with",
"LCA,",
"either",
"homozygously",
"or",
"in",
"combination",
"with",
"a",
"second",
"deleterious",
"mutation",
"on",
"the",
"other",
"allele.",
"CEP290",
" ",
"mutations",
"therefore",
"represent",
"one",
"of",
"the",
"most",
"frequent",
"causes",
"of",
"LCA",
"identified",
"so",
"far."
] | [
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Mutations in the CEP290 ( NPHP6 ) gene are a frequent cause of Leber congenital amaurosis. Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein ( CEP290 ). The defect is caused by an intronic mutation ( c.2991+1655A-->G ) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far. | [
2,
3527,
1922,
1920,
17008,
24069,
12,
25556,
26974,
13,
2359,
2032,
43,
6439,
3936,
1927,
2071,
2361,
9901,
2150,
6346,
4870,
18,
2071,
2361,
9901,
2150,
6346,
4870,
12,
23077,
13,
1977,
2340,
1927,
1920,
2730,
5092,
1927,
7238,
19880,
18,
1942,
5699,
16,
3527,
1922,
5066,
2628,
2162,
2252,
2910,
16,
2154,
4084,
5042,
1958,
3993,
3607,
9,
1927,
23077,
2919,
18,
2038,
6579,
1920,
3299,
7374,
1922,
43,
29684,
19616,
2080,
23077,
17,
4218,
3416,
2037,
26180,
1930,
2899,
43,
10708,
7374,
1922,
43,
2359,
5797,
43,
14783,
4229,
2213,
12,
17008,
24069,
13,
18,
1920,
7374,
1977,
4189,
2007,
1925,
20341,
3979,
12,
45,
18,
22967,
1009,
15,
14113,
9422,
17,
17,
34,
49,
13,
1988,
15628,
43,
3206,
10708,
17,
6282,
3200,
1930,
17520,
43,
21565,
7049,
1922,
1920,
17008,
24069,
16716,
3146,
18,
2052,
3979,
1982,
3330,
1922,
2641,
12,
2900,
9,
13,
1927,
5439,
10295,
2132,
1956,
23077,
16,
3108,
9419,
1954,
2014,
1922,
3921,
1956,
43,
2812,
12524,
3979,
1990,
1920,
2303,
5465,
18,
17008,
24069,
3527,
2955,
3015,
2340,
1927,
1920,
2501,
6439,
5092,
1927,
23077,
2899,
2577,
5108,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
7599640 | [
"Mutations",
"of",
"the",
"iduronate-2-sulfatase",
"gene",
"on",
"a",
"T146T",
"background",
"in",
"three",
"patients",
"with",
"Hunter",
"syndrome."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Mutations of the iduronate-2-sulfatase gene on a T146T background in three patients with Hunter syndrome. | [
2,
3527,
1927,
1920,
2313,
10366,
2010,
17,
22,
17,
5141,
7234,
2359,
1990,
43,
6197,
7772,
1031,
3872,
1922,
2559,
2132,
1956,
27684,
4741,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
16671095 | [
"A",
"homozygous",
"ZMPSTE24",
" ",
"null",
"mutation",
"in",
"combination",
"with",
"a",
"heterozygous",
"mutation",
"in",
"the",
"LMNA",
" ",
"gene",
"causes",
"Hutchinson-Gilford",
"progeria",
"syndrome",
"(HGPS):",
"insights",
"into",
"the",
"pathophysiology",
"of",
"HGPS.",
"Hutchinson-Gilford",
"progeria",
"syndrome",
"(HGPS)",
"is",
"a",
"rare",
"premature",
"aging",
"disorder",
"normally",
"caused",
"by",
"a",
"spontaneous",
"heterozygous",
"mutation",
"in",
"the",
"LMNA",
" ",
"gene",
"that",
"codes",
"for",
"the",
"nuclear",
"lamina",
"protein",
"lamin",
"A",
".",
"Several",
"enzymes",
"are",
"involved",
"in",
"the",
"processing",
"of",
"its",
"precursor,",
"prelamin",
"A,",
"to",
"the",
"mature",
"lamin",
"A.",
"A",
"functional",
"knockout",
"of",
"one",
"of",
"the",
"enzymes",
"involved",
"in",
"prelamin",
"A",
"processing,",
"the",
"zinc",
"metalloprotease",
"ZMPSTE24",
",",
"causes",
"an",
"even",
"more",
"severe",
"disorder",
"with",
"early",
"neonatal",
"death",
"described",
"as",
"restrictive",
"dermatopathy",
"(RD).",
"This",
"work",
"describes",
"a",
"HGPS",
"patient",
"with",
"a",
"combined",
"defect",
"of",
"a",
"homozygous",
"loss-of-function",
"mutation",
"in",
"the",
"ZMPSTE24",
" ",
"gene",
"and",
"a",
"heterozygous",
"mutation",
"in",
"the",
"LMNA",
" ",
"gene",
"that",
"results",
"in",
"a",
"C-terminal",
"elongation",
"of",
"the",
"final",
"lamin",
"A",
".",
"Whereas",
"the",
"loss",
"of",
"function",
"mutation",
"of",
"ZMPSTE24",
" ",
"normally",
"results",
"in",
"lethal",
"RD,",
"the",
"truncation",
"of",
"LMNA",
" ",
"seems",
"to",
"be",
"a",
"salvage",
"alteration",
"alleviating",
"the",
"clinical",
"picture",
"to",
"the",
"HGPS",
"phenotype.",
"The",
"mutations",
"of",
"our",
"patient",
"indicate",
"that",
"farnesylated",
"prelamin",
"A",
"is",
"the",
"deleterious",
"agent",
"leading",
"to",
"the",
"HGPS",
"phenotype,",
"which",
"gives",
"further",
"insights",
"into",
"the",
"pathophysiology",
"of",
"the",
"disorder."
] | [
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder normally caused by a spontaneous heterozygous mutation in the LMNA gene that codes for the nuclear lamina protein lamin A . Several enzymes are involved in the processing of its precursor, prelamin A, to the mature lamin A. A functional knockout of one of the enzymes involved in prelamin A processing, the zinc metalloprotease ZMPSTE24 , causes an even more severe disorder with early neonatal death described as restrictive dermatopathy (RD). This work describes a HGPS patient with a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that results in a C-terminal elongation of the final lamin A . Whereas the loss of function mutation of ZMPSTE24 normally results in lethal RD, the truncation of LMNA seems to be a salvage alteration alleviating the clinical picture to the HGPS phenotype. The mutations of our patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder. | [
2,
43,
9419,
21748,
2523,
2057,
4561,
6764,
3979,
1922,
3921,
1956,
43,
9589,
3979,
1922,
1920,
7735,
2175,
2359,
5092,
21033,
28964,
5810,
17,
16476,
8331,
1965,
4938,
2126,
4741,
12,
7175,
2523,
13,
30,
8486,
2460,
1920,
11985,
1927,
7175,
2523,
18,
21033,
28964,
5810,
17,
16476,
8331,
1965,
4938,
2126,
4741,
12,
7175,
2523,
13,
1977,
43,
5844,
9839,
6619,
4770,
7885,
4189,
2007,
43,
6242,
9589,
3979,
1922,
1920,
7735,
2175,
2359,
1988,
9756,
1958,
1920,
4254,
14310,
2213,
7962,
43,
18,
2980,
5038,
2032,
3286,
1922,
1920,
4587,
1927,
2496,
7897,
16,
2097,
10082,
1921,
43,
16,
1942,
1920,
6665,
7962,
43,
18,
43,
3183,
7949,
1927,
2340,
1927,
1920,
5038,
3286,
1922,
2097,
10082,
1921,
43,
4587,
16,
1920,
7997,
28629,
2051,
21748,
2523,
2057,
4561,
16,
5092,
1925,
3385,
2253,
4010,
4770,
1956,
3120,
7985,
3539,
2910,
1966,
18567,
13467,
6522,
12,
8695,
13,
18,
2052,
2778,
9845,
43,
7175,
2523,
2774,
1956,
43,
4252,
7374,
1927,
43,
9419,
3257,
17,
1927,
17,
2347,
3979,
1922,
1920,
21748,
2523,
2057,
4561,
2359,
1930,
43,
9589,
3979,
1922,
1920,
7735,
2175,
2359,
1988,
2274,
1922,
43,
45,
17,
4262,
9971,
1927,
1920,
3948,
7962,
43,
18,
3417,
1920,
3257,
1927,
2347,
3979,
1927,
21748,
2523,
2057,
4561,
7885,
2274,
1922,
10470,
8695,
16,
1920,
18802,
1927,
7735,
2175,
6123,
1942,
1998,
43,
17577,
10076,
12054,
2287,
1920,
2535,
10213,
1942,
1920,
7175,
2523,
4629,
18,
1920,
3527,
1927,
2342,
2774,
3579,
1988,
24281,
4336,
2097,
10082,
1921,
43,
1977,
1920,
12524,
5899,
4523,
1942,
1920,
7175,
2523,
4629,
16,
2154,
10006,
2520,
8486,
2460,
1920,
11985,
1927,
1920,
4770,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8751870 | [
"Family",
"study",
"and",
"segregation",
"analysis",
"of",
"Tourette",
"syndrome:",
"evidence",
"for",
"a",
"mixed",
"model",
"of",
"inheritance.",
"To",
"investigate",
"the",
"transmission",
"of",
"Tourette",
"syndrome",
"(TS)",
"and",
"associated",
"disorders",
"within",
"families,",
"complex",
"segregation",
"analysis",
"was",
"performed",
"on",
"family",
"study",
"data",
"obtained",
"from",
"53",
"independently",
"ascertained",
"children",
"and",
"adolescents",
"with",
"TS",
"and",
"their",
"154",
"first-degree",
"relatives.",
"The",
"results",
"suggest",
"that",
"the",
"susceptibility",
"for",
"TS",
"is",
"conveyed",
"by",
"a",
"major",
"locus",
"in",
"combination",
"with",
"a",
"multifactorial",
"background.",
"Other",
"models",
"of",
"inheritance",
"were",
"definitively",
"rejected,",
"including",
"strictly",
"polygenic",
"models,",
"all",
"single",
"major",
"locus",
"models,",
"and",
"mixed",
"models",
"with",
"dominant",
"and",
"recessive",
"major",
"loci.",
"The",
"frequency",
"of",
"the",
"TS",
"susceptibility",
"allele",
"was",
"estimated",
"to",
"be",
".01.",
"The",
"major",
"locus",
"accounts",
"for",
"over",
"half",
"of",
"the",
"phenotypic",
"variance",
"for",
"TS,",
"whereas",
"the",
"multifactorial",
"background",
"accounts",
"for",
"approximately",
"40%",
"of",
"phenotypic",
"variance.",
"Penetrance",
"estimates",
"suggest",
"that",
"all",
"individuals",
"homozygous",
"for",
"the",
"susceptibility",
"allele",
"at",
"the",
"major",
"locus",
"are",
"affected,",
"whereas",
"only",
"2.2%",
"of",
"males",
"and",
"0.3%",
"of",
"females",
"heterozygous",
"at",
"the",
"major",
"locus",
"are",
"affected.",
"Of",
"individuals",
"affected",
"with",
"TS,",
"approximately",
"62%",
"are",
"heterozygous",
"and",
"approximately",
"38%",
"are",
"homozygous",
"at",
"the",
"major",
"locus.",
"While",
"none",
"of",
"the",
"families",
"had",
"two",
"parents",
"affected",
"with",
"TS,",
"19%",
"of",
"families",
"had",
"two",
"parents",
"affected",
"with",
"the",
"broader,",
"phenotype,",
"which",
"includes",
"TS,",
"chronic",
"tic",
"disorder,",
"or",
"obsessive-compulsive",
"disorder."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance. To investigate the transmission of Tourette syndrome (TS) and associated disorders within families, complex segregation analysis was performed on family study data obtained from 53 independently ascertained children and adolescents with TS and their 154 first-degree relatives. The results suggest that the susceptibility for TS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitively rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the TS susceptibility allele was estimated to be .01. The major locus accounts for over half of the phenotypic variance for TS, whereas the multifactorial background accounts for approximately 40% of phenotypic variance. Penetrance estimates suggest that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with TS, approximately 62% are heterozygous and approximately 38% are homozygous at the major locus. While none of the families had two parents affected with TS, 19% of families had two parents affected with the broader, phenotype, which includes TS, chronic tic disorder, or obsessive-compulsive disorder. | [
2,
3416,
2161,
1930,
12707,
2333,
1927,
24097,
6488,
4741,
30,
3095,
1958,
43,
4985,
2322,
1927,
15762,
18,
1942,
4482,
1920,
5303,
1927,
24097,
6488,
4741,
12,
4894,
13,
1930,
2458,
4414,
2651,
5767,
16,
2796,
12707,
2333,
1982,
2593,
1990,
3416,
2161,
2230,
2926,
2037,
4522,
6407,
19231,
3069,
1930,
6464,
1956,
4894,
1930,
2310,
14396,
2561,
17,
4647,
12280,
18,
1920,
2274,
3220,
1988,
1920,
6461,
1958,
4894,
1977,
20267,
1919,
2007,
43,
3044,
6730,
1922,
3921,
1956,
43,
19291,
3872,
18,
2303,
3130,
1927,
15762,
1985,
25395,
18631,
16,
2710,
14470,
27697,
3130,
16,
2136,
2957,
3044,
6730,
3130,
16,
1930,
4985,
3130,
1956,
6379,
1930,
13992,
3044,
6971,
18,
1920,
3528,
1927,
1920,
4894,
6461,
5465,
1982,
4185,
1942,
1998,
18,
3287,
18,
1920,
3044,
6730,
11053,
1958,
2338,
4768,
1927,
1920,
8189,
5623,
1958,
4894,
16,
3417,
1920,
19291,
3872,
11053,
1958,
3993,
3040,
9,
1927,
8189,
5623,
18,
22035,
5280,
3220,
1988,
2136,
3445,
9419,
1958,
1920,
6461,
5465,
2019,
1920,
3044,
6730,
2032,
4218,
16,
3417,
2444,
22,
18,
22,
9,
1927,
5129,
1930,
20,
18,
23,
9,
1927,
5027,
9589,
2019,
1920,
3044,
6730,
2032,
4218,
18,
1927,
3445,
4218,
1956,
4894,
16,
3993,
5374,
9,
2032,
9589,
1930,
3993,
3738,
9,
2032,
9419,
2019,
1920,
3044,
6730,
18,
2679,
6046,
1927,
1920,
5767,
2430,
2288,
5853,
4218,
1956,
4894,
16,
2282,
9,
1927,
5767,
2430,
2288,
5853,
4218,
1956,
1920,
11462,
16,
4629,
16,
2154,
5921,
4894,
16,
3724,
18298,
4770,
16,
2014,
25555,
17,
21543,
4770,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20826270 | [
"Protein",
"tyrosine",
"phosphatase",
"PTPN14",
"Protein",
"tyrosine",
"phosphatase",
" ",
"PTPN14",
"is",
"a",
"regulator",
"of",
"lymphatic",
"function",
"and",
"choanal",
"development",
"in",
"humans.",
"The",
"lymphatic",
"vasculature",
"is",
"essential",
"for",
"the",
"recirculation",
"of",
"extracellular",
"fluid,",
"fat",
"absorption,",
"and",
"immune",
"function",
"and",
"as",
"a",
"route",
"of",
"tumor",
"metastasis.",
"The",
"dissection",
"of",
"molecular",
"mechanisms",
"underlying",
"lymphangiogenesis",
"has",
"been",
"accelerated",
"by",
"the",
"identification",
"of",
"tissue-specific",
"lymphatic",
"endothelial",
"markers",
"and",
"the",
"study",
"of",
"congenital",
"lymphedema",
"syndromes.",
"We",
"report",
"the",
"results",
"of",
"genetic",
"analyses",
"of",
"a",
"kindred",
"inheriting",
"a",
"unique",
"autosomal-recessive",
"lymphedema-choanal",
"atresia",
"syndrome.",
"These",
"studies",
"establish",
"linkage",
"of",
"the",
"trait",
"to",
"chromosome",
"1q32-q41",
"and",
"identify",
"a",
"loss-of-function",
"mutation",
"in",
"PTPN14",
",",
"which",
"encodes",
"a",
"nonreceptor",
"tyrosine",
"phosphatase.",
"The",
"causal",
"role",
"of",
"PTPN14",
" ",
"deficiency",
"was",
"confirmed",
"by",
"the",
"generation",
"of",
"a",
"murine",
"Ptpn14",
" ",
"gene",
"trap",
"model",
"that",
"manifested",
"lymphatic",
"hyperplasia",
"with",
"lymphedema.",
"Biochemical",
"studies",
"revealed",
"a",
"potential",
"interaction",
"between",
"PTPN14",
" ",
"and",
"the",
"vascular",
"endothelial",
"growth",
"factor",
"receptor",
"3",
" ",
"(",
"VEGFR3",
"),",
"a",
"receptor",
"tyrosine",
"kinase",
"essential",
"for",
"lymphangiogenesis.",
"These",
"results",
"suggest",
"a",
"unique",
"and",
"conserved",
"role",
"for",
"PTPN14",
" ",
"in",
"the",
"regulation",
"of",
"lymphatic",
"development",
"in",
"mammals",
"and",
"a",
"nonconserved",
"role",
"in",
"choanal",
"development",
"in",
"humans."
] | [
0,
0,
0,
1,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
2,
2,
2,
2,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Protein tyrosine phosphatase PTPN14 Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. The lymphatic vasculature is essential for the recirculation of extracellular fluid, fat absorption, and immune function and as a route of tumor metastasis. The dissection of molecular mechanisms underlying lymphangiogenesis has been accelerated by the identification of tissue-specific lymphatic endothelial markers and the study of congenital lymphedema syndromes. We report the results of genetic analyses of a kindred inheriting a unique autosomal-recessive lymphedema-choanal atresia syndrome. These studies establish linkage of the trait to chromosome 1q32-q41 and identify a loss-of-function mutation in PTPN14 , which encodes a nonreceptor tyrosine phosphatase. The causal role of PTPN14 deficiency was confirmed by the generation of a murine Ptpn14 gene trap model that manifested lymphatic hyperplasia with lymphedema. Biochemical studies revealed a potential interaction between PTPN14 and the vascular endothelial growth factor receptor 3 ( VEGFR3 ), a receptor tyrosine kinase essential for lymphangiogenesis. These results suggest a unique and conserved role for PTPN14 in the regulation of lymphatic development in mammals and a nonconserved role in choanal development in humans. | [
2,
2213,
6941,
8167,
28207,
3745,
2213,
6941,
8167,
28207,
3745,
1977,
43,
7888,
1927,
13388,
2347,
1930,
4551,
10927,
2740,
1922,
5209,
18,
1920,
13388,
13040,
1977,
4415,
1958,
1920,
2090,
13220,
2281,
1927,
5329,
5466,
16,
3777,
6726,
16,
1930,
3743,
2347,
1930,
1966,
43,
9629,
1927,
2798,
5967,
18,
1920,
10819,
1927,
3272,
3531,
5030,
29065,
3761,
2258,
2252,
10843,
2007,
1920,
4824,
1927,
2960,
17,
2487,
13388,
5003,
4432,
1930,
1920,
2161,
1927,
9901,
3541,
16670,
12688,
18,
2038,
3809,
1920,
2274,
1927,
3299,
3247,
1927,
43,
6925,
3510,
7232,
3658,
43,
5008,
13027,
17,
13992,
3541,
16670,
17,
4551,
10927,
29211,
4741,
18,
2144,
2351,
5389,
8611,
1927,
1920,
8823,
1942,
5597,
28798,
6763,
17,
59,
8099,
1930,
3512,
43,
3257,
17,
1927,
17,
2347,
3979,
1922,
28207,
3745,
16,
2154,
9937,
43,
28309,
3342,
1924,
6941,
8167,
18,
1920,
9263,
2770,
1927,
28207,
3745,
6179,
1982,
3982,
2007,
1920,
4841,
1927,
43,
7135,
28207,
3745,
2359,
10947,
2322,
1988,
16687,
13388,
13095,
1956,
3541,
16670,
18,
6503,
2351,
3404,
43,
2889,
2835,
2192,
28207,
3745,
1930,
1920,
4541,
5003,
2905,
2991,
3148,
23,
12,
18828,
1010,
13,
16,
43,
3148,
6941,
4016,
4415,
1958,
29065,
3761,
18,
2144,
2274,
3220,
43,
5008,
1930,
5305,
2770,
1958,
28207,
3745,
1922,
1920,
3640,
1927,
13388,
2740,
1922,
9902,
1930,
43,
9341,
2101,
4633,
2770,
1922,
4551,
10927,
2740,
1922,
5209,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
1,
2,
2,
2,
2,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1598907 | [
"A",
"missense",
"mutation",
"(Trp86----Arg)",
"in",
"exon",
"3",
"of",
"the",
"lipoprotein",
"lipase",
"Trp86----Arg",
")",
"in",
"exon",
"3",
"of",
"the",
"lipoprotein",
"lipase",
"gene:",
"a",
"cause",
"of",
"familial",
"chylomicronemia.",
"We",
"have",
"investigated",
"a",
"patient",
"of",
"English",
"ancestry",
"with",
"familial",
"chylomicronemia",
"caused",
"by",
"lipoprotein",
"lipase",
" ",
"(",
"LPL",
")",
"deficiency.",
"DNA",
"sequence",
"analysis",
"of",
"all",
"exons",
"and",
"intron-exon",
"boundaries",
"of",
"the",
"LPL",
" ",
"gene",
"identified",
"two",
"single-base",
"mutations,",
"a",
"T----C",
"transition",
"for",
"codon",
"86",
"(TGG)",
"at",
"nucleotide",
"511,",
"resulting",
"in",
"a",
"Trp86----Arg",
"T----C",
"transition",
"for",
"codon",
"86",
"(TGG)",
"at",
"nucleotide",
"511",
",",
"resulting",
"in",
"a",
"Trp86----Arg",
"substitution,",
"and",
"a",
"C----T",
"transition",
"at",
"nucleotide",
"571",
",",
"involving",
"the",
"codon",
"CAG",
"encoding",
"Gln106",
"and",
"producing",
"Gln106----Stop",
",",
"a",
"mutation",
"described",
"by",
"Emi",
"et",
"al.",
"The",
"functional",
"significance",
"of",
"the",
"two",
"mutations",
"was",
"confirmed",
"by",
"in",
"vitro",
"expression",
"and",
"enzyme",
"activity",
"assays",
"of",
"the",
"mutant",
"LPL",
".",
"Linkage",
"analysis",
"established",
"that",
"the",
"patient",
"is",
"a",
"compound",
"heterozygote",
"for",
"the",
"two",
"mutations.",
"The",
"Trp86----Arg",
" ",
"mutation",
"in",
"exon",
"3",
"is",
"the",
"first",
"natural",
"mutation",
"identified",
"outside",
"exons",
"4-6,",
"which",
"encompass",
"the",
"catalytic",
"triad",
"residues."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A missense mutation (Trp86----Arg) in exon 3 of the lipoprotein lipase Trp86----Arg ) in exon 3 of the lipoprotein lipase gene: a cause of familial chylomicronemia. We have investigated a patient of English ancestry with familial chylomicronemia caused by lipoprotein lipase ( LPL ) deficiency. DNA sequence analysis of all exons and intron-exon boundaries of the LPL gene identified two single-base mutations, a T----C transition for codon 86 (TGG) at nucleotide 511, resulting in a Trp86----Arg T----C transition for codon 86 (TGG) at nucleotide 511 , resulting in a Trp86----Arg substitution, and a C----T transition at nucleotide 571 , involving the codon CAG encoding Gln106 and producing Gln106----Stop , a mutation described by Emi et al. The functional significance of the two mutations was confirmed by in vitro expression and enzyme activity assays of the mutant LPL . Linkage analysis established that the patient is a compound heterozygote for the two mutations. The Trp86----Arg mutation in exon 3 is the first natural mutation identified outside exons 4-6, which encompass the catalytic triad residues. | [
2,
43,
13519,
3979,
12,
7259,
11617,
17,
17,
17,
17,
4582,
13,
1922,
7049,
23,
1927,
1920,
9694,
16653,
7259,
11617,
17,
17,
17,
17,
4582,
13,
1922,
7049,
23,
1927,
1920,
9694,
16653,
2359,
30,
43,
3936,
1927,
11444,
2016,
2199,
22980,
19319,
2126,
18,
2038,
2162,
3845,
43,
2774,
1927,
8998,
15419,
1956,
11444,
2016,
2199,
22980,
19319,
2126,
4189,
2007,
9694,
16653,
12,
20880,
13,
6179,
18,
2678,
3244,
2333,
1927,
2136,
10419,
1930,
10444,
17,
7049,
11471,
1927,
1920,
20880,
2359,
2899,
2288,
2957,
17,
5170,
3527,
16,
43,
62,
17,
17,
17,
17,
45,
4832,
1958,
8905,
5713,
12,
23316,
13,
2019,
5489,
27725,
16,
3864,
1922,
43,
7259,
11617,
17,
17,
17,
17,
4582,
62,
17,
17,
17,
17,
45,
4832,
1958,
8905,
5713,
12,
23316,
13,
2019,
5489,
27725,
16,
3864,
1922,
43,
7259,
11617,
17,
17,
17,
17,
4582,
6636,
16,
1930,
43,
45,
17,
17,
17,
17,
62,
4832,
2019,
5489,
4786,
1009,
16,
5884,
1920,
8905,
13415,
5797,
15236,
16551,
1930,
7144,
15236,
16551,
17,
17,
17,
17,
6875,
16,
43,
3979,
2910,
2007,
2391,
1033,
2140,
1969,
18,
1920,
3183,
4550,
1927,
1920,
2288,
3527,
1982,
3982,
2007,
1922,
3596,
2294,
1930,
4113,
2455,
4614,
1927,
1920,
3606,
20880,
18,
8611,
2333,
4379,
1988,
1920,
2774,
1977,
43,
3547,
28070,
1958,
1920,
2288,
3527,
18,
1920,
7259,
11617,
17,
17,
17,
17,
4582,
3979,
1922,
7049,
23,
1977,
1920,
2561,
4613,
3979,
2899,
7008,
10419,
24,
17,
26,
16,
2154,
11274,
1920,
6804,
21845,
4248,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
16673358 | [
"The",
"spectrum",
"of",
"WRN",
"mutations",
"in",
"Werner",
"syndrome",
"patients.",
"The",
"International",
"Registry",
"of",
"Werner",
"syndrome",
"(www.wernersyndrome.org)",
"has",
"been",
"providing",
"molecular",
"diagnosis",
"of",
"the",
"Werner",
"syndrome",
"(WS)",
"for",
"the",
"past",
"decade.",
"The",
"present",
"communication",
"summarizes,",
"from",
"among",
"99",
"WS",
"subjects,",
"the",
"spectrum",
"of",
"50",
"distinct",
"mutations",
"discovered",
"by",
"our",
"group",
"and",
"by",
"others",
"since",
"the",
"WRN",
" ",
"gene",
"(also",
"called",
"RECQL2",
" ",
"or",
"REQ3",
")",
"was",
"first",
"cloned",
"in",
"1996;",
"25",
"of",
"these",
"have",
"not",
"previously",
"been",
"published.",
"All",
"WRN",
" ",
"mutations",
"reported",
"thus",
"far",
"have",
"resulted",
"in",
"the",
"elimination",
"of",
"the",
"nuclear",
"localization",
"signal",
"at",
"the",
"C-terminus",
"of",
"the",
"protein,",
"precluding",
"functional",
"interactions",
"in",
"the",
"nucleus;",
"thus,",
"all",
"could",
"be",
"classified",
"as",
"null",
"mutations.",
"We",
"now",
"report",
"two",
"new",
"mutations",
"in",
"the",
"N-terminus",
"that",
"result",
"in",
"instability",
"of",
"the",
"WRN",
" ",
"protein.",
"Clinical",
"data",
"confirm",
"that",
"the",
"most",
"penetrant",
"phenotype",
"is",
"bilateral",
"ocular",
"cataracts.",
"Other",
"cardinal",
"signs",
"were",
"seen",
"in",
"more",
"than",
"95%",
"of",
"the",
"cases.",
"The",
"median",
"age",
"of",
"death,",
"previously",
"reported",
"to",
"be",
"in",
"the",
"range",
"of",
"46-48",
"years,",
"is",
"54",
"years.",
"Lymphoblastoid",
"cell",
"lines",
"(LCLs)",
"have",
"been",
"cryopreserved",
"from",
"the",
"majority",
"of",
"our",
"index",
"cases,",
"including",
"material",
"from",
"nuclear",
"pedigrees.",
"These,",
"as",
"well",
"as",
"inducible",
"and",
"complemented",
"hTERT",
"(catalytic",
"subunit",
"of",
"human",
"telomerase)",
"immortalized",
"skin",
"fibroblast",
"cell",
"lines",
"are",
"available",
"to",
"qualified",
"investigators."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The spectrum of WRN mutations in Werner syndrome patients. The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3 ) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators. | [
2,
1920,
5648,
1927,
28612,
3527,
1922,
22210,
3239,
4741,
2132,
18,
1920,
6019,
10557,
1927,
22210,
3239,
4741,
12,
6425,
18,
22210,
5781,
2304,
3883,
2225,
18,
2908,
13,
2258,
2252,
5453,
3272,
3574,
1927,
1920,
22210,
3239,
4741,
12,
12369,
13,
1958,
1920,
5375,
10468,
18,
1920,
2481,
6396,
14934,
16,
2037,
2706,
4922,
12369,
3297,
16,
1920,
5648,
1927,
2761,
4493,
3527,
8117,
2007,
2342,
2210,
1930,
2007,
4991,
3328,
1920,
28612,
2359,
12,
2222,
6043,
2090,
18404,
1028,
2014,
1964,
1055,
1010,
13,
1982,
2561,
8283,
1922,
6388,
31,
2637,
1927,
2144,
2162,
2084,
3024,
2252,
4586,
18,
2136,
28612,
3527,
2568,
2842,
5108,
2162,
4306,
1922,
1920,
9570,
1927,
1920,
4254,
5363,
2733,
2019,
1920,
45,
17,
7822,
1927,
1920,
2213,
16,
8395,
9062,
3183,
3719,
1922,
1920,
5607,
31,
2842,
16,
2136,
2578,
1998,
5947,
1966,
6764,
3527,
18,
2038,
5195,
3809,
2288,
2814,
3527,
1922,
1920,
56,
17,
7822,
1988,
3211,
1922,
9557,
1927,
1920,
28612,
2213,
18,
2535,
2230,
4763,
1988,
1920,
2501,
8126,
2031,
4629,
1977,
7787,
10046,
14833,
1036,
18,
2303,
27529,
6879,
1985,
3945,
1922,
2253,
2254,
3002,
9,
1927,
1920,
2919,
18,
1920,
4181,
2632,
1927,
3539,
16,
3024,
2568,
1942,
1998,
1922,
1920,
3109,
1927,
4182,
17,
3427,
2739,
16,
1977,
4584,
2739,
18,
3541,
7439,
2642,
2024,
3557,
12,
5236,
4668,
13,
2162,
2252,
26200,
2037,
1920,
4827,
1927,
2342,
3867,
2919,
16,
2710,
3485,
2037,
4254,
22336,
1036,
18,
2144,
16,
1966,
2486,
1966,
9376,
1930,
17849,
20824,
12,
6804,
5903,
1927,
2616,
14616,
13,
18987,
4407,
10541,
2024,
3557,
2032,
3322,
1942,
19020,
9427,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
1,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8829650 | [
"Molecular",
"basis",
"of",
"congenital",
"erythropoietic",
"porphyria:",
"mutations",
"in",
"the",
"human",
"uroporphyrinogen",
"III",
"synthase",
" ",
"gene.",
"Congenital",
"erythropoietic",
"porphyria",
"(CEP)",
"is",
"an",
"autosomal",
"recessive",
"inborn",
"error",
"of",
"metabolism",
"that",
"results",
"from",
"the",
"markedly",
"deficient",
"activity",
"of",
"the",
"fourth",
"enzyme",
"in",
"the",
"heme",
"biosynthetic",
"pathway,",
"uroporphyrinogen",
"III",
"synthase",
"(URO-synthase).",
"To",
"date,",
"17",
"mutations",
"have",
"been",
"described",
"including",
"11",
"missense,",
"one",
"nonsense,",
"two",
"mRNA",
"splicing",
"defects,",
"one",
"deletion",
"and",
"two",
"coding",
"region",
"insertions.",
"Most",
"mutations",
"have",
"been",
"identified",
"in",
"one",
"or",
"a",
"few",
"unrelated",
"families",
"with",
"the",
"exception",
"of",
"C73R",
" ",
"and",
"L4F",
" ",
"which",
"occurred",
"in",
"29.6%",
"and",
"9.3%",
"of",
"the",
"54",
"mutant",
"alleles",
"studied,",
"respectively.",
"Interestingly,",
"analysis",
"of",
"the",
"mutant",
"alleles",
"identified",
"only",
"83%",
"of",
"the",
"causative",
"mutations,",
"suggesting",
"that",
"about",
"20%",
"of",
"the",
"mutations",
"causing",
"CEP",
"lie",
"elsewhere",
"in",
"the",
"gene.",
"Of",
"note,",
"mutation",
"V82F",
",",
"resulting",
"from",
"a",
"G",
"to",
"T",
"transversion",
"of",
"the",
"last",
"nucleotide",
"of",
"exon",
"4,",
" ",
"caused",
"both",
"a",
"missense",
"mutation",
"and",
"an",
"aberrantly",
"spliced",
"RNA",
"transcript.",
"Prokaryotic",
"expression",
"of",
"the",
"mutant",
"URO-synthase",
"alleles",
"identified",
"those",
"with",
"significant",
"residual",
"activity,",
"thereby",
"permitting",
"genotype/phenotype",
"predictions",
"for",
"this",
"clinically",
"heterogeneous",
"disease."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene. Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of the fourth enzyme in the heme biosynthetic pathway, uroporphyrinogen III synthase (URO-synthase). To date, 17 mutations have been described including 11 missense, one nonsense, two mRNA splicing defects, one deletion and two coding region insertions. Most mutations have been identified in one or a few unrelated families with the exception of C73R and L4F which occurred in 29.6% and 9.3% of the 54 mutant alleles studied, respectively. Interestingly, analysis of the mutant alleles identified only 83% of the causative mutations, suggesting that about 20% of the mutations causing CEP lie elsewhere in the gene. Of note, mutation V82F , resulting from a G to T transversion of the last nucleotide of exon 4, caused both a missense mutation and an aberrantly spliced RNA transcript. Prokaryotic expression of the mutant URO-synthase alleles identified those with significant residual activity, thereby permitting genotype/phenotype predictions for this clinically heterogeneous disease. | [
2,
3272,
4859,
1927,
9901,
23288,
2002,
17376,
3553,
2126,
30,
3527,
1922,
1920,
2616,
14984,
2074,
25818,
5572,
2404,
4337,
8921,
2359,
18,
9901,
23288,
2002,
17376,
3553,
2126,
12,
17008,
13,
1977,
1925,
13027,
13992,
1922,
23419,
4622,
1927,
4714,
1988,
2274,
2037,
1920,
7686,
5778,
2455,
1927,
1920,
8776,
4113,
1922,
1920,
10954,
14041,
3374,
16,
14984,
2074,
25818,
5572,
2404,
4337,
8921,
12,
14984,
17,
8921,
13,
18,
1942,
5699,
16,
2752,
3527,
2162,
2252,
2910,
2710,
2513,
13519,
16,
2340,
19605,
16,
2288,
3616,
8490,
6007,
16,
2340,
5541,
1930,
2288,
5804,
3031,
15135,
18,
2501,
3527,
2162,
2252,
2899,
1922,
2340,
2014,
43,
3855,
10295,
5767,
1956,
1920,
7541,
1927,
19677,
1010,
1005,
1930,
16546,
1038,
2154,
4807,
1922,
3230,
18,
26,
9,
1930,
29,
18,
23,
9,
1927,
1920,
4584,
3606,
7096,
3942,
16,
2763,
18,
4945,
16,
2333,
1927,
1920,
3606,
7096,
2899,
2444,
5893,
9,
1927,
1920,
13939,
3527,
16,
3783,
1988,
3001,
2036,
9,
1927,
1920,
3527,
7538,
17008,
14958,
10132,
1922,
1920,
2359,
18,
1927,
4725,
16,
3979,
64,
11715,
1038,
16,
3864,
2037,
43,
49,
1942,
62,
22916,
2001,
1927,
1920,
4691,
5489,
1927,
7049,
24,
16,
4189,
2321,
43,
13519,
3979,
1930,
1925,
30412,
17459,
3146,
5291,
18,
21545,
2294,
1927,
1920,
3606,
14984,
17,
8921,
7096,
2899,
2690,
1956,
2228,
6615,
2455,
16,
6113,
25180,
5619,
19,
4629,
8677,
1958,
2052,
5908,
8538,
2573,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
3,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
10649495 | [
"Glucocerebrosidase",
" ",
"gene",
"mutations",
"in",
"patients",
"with",
"type",
"2",
"Gaucher",
"disease.",
"Gaucher",
"disease,",
"the",
"most",
"common",
"lysosomal",
"storage",
"disorder,",
"results",
"from",
"the",
"inherited",
"deficiency",
"of",
"the",
"enzyme",
"glucocerebrosidase.",
"Three",
"clinical",
"types",
"are",
"recognized:",
"type",
"1,",
"non-neuronopathic;",
"type",
"2,",
"acute",
"neuronopathic;",
"and",
"type",
"3,",
"subacute",
"neuronopathic.",
"Type",
"2",
"Gaucher",
"disease,",
"the",
"rarest",
"type,",
"is",
"progressive",
"and",
"fatal.",
"We",
"have",
"performed",
"molecular",
"analyses",
"of",
"a",
"cohort",
"of",
"31",
"patients",
"with",
"type",
"2",
"Gaucher",
"disease.",
"The",
"cases",
"studied",
"included",
"fetuses",
"presenting",
"prenatally",
"with",
"hydrops",
"fetalis,",
"infants",
"with",
"the",
"collodion",
"baby",
"phenotype,",
"and",
"infants",
"diagnosed",
"after",
"several",
"months",
"of",
"life.",
"All",
"62",
"mutant",
"glucocerebrosidase",
"(GBA)",
"alleles",
"were",
"identified.",
"Thirty-three",
"different",
"mutant",
"alleles",
"were",
"found,",
"including",
"point",
"mutations,",
"splice",
"junction",
"mutations,",
"deletions,",
"fusion",
"alleles",
"and",
"recombinant",
"alleles.",
"Eleven",
"novel",
"mutations",
"were",
"identified",
"in",
"these",
"patients:",
"R131L",
",",
"H255Q",
",",
"R285H",
",",
"S196P",
",",
"H311R",
",",
"c.330delA",
",",
"V398F",
",",
"F259L",
",",
"c.533delC",
",",
"Y304C",
" ",
"and",
"A190E",
".",
"Mutation",
"L444P",
" ",
"was",
"found",
"on",
"25",
"patient",
"alleles.",
"Southern",
"blots",
"and",
"direct",
"sequencing",
"demonstrated",
"that",
"mutation",
"L444P",
" ",
"occurred",
"alone",
"on",
"9",
"alleles,",
"with",
"E326K",
" ",
"on",
"one",
"allele",
"and",
"as",
"part",
"of",
"a",
"recombinant",
"allele",
"on",
"15",
"alleles.",
"There",
"were",
"no",
"homozygotes",
"for",
"point",
"mutation",
"L444P",
".",
"The",
"recombinant",
"alleles",
"that",
"included",
"L444P",
"glucocerebrosidase",
" ",
"(",
"GBA",
")",
"alleles",
"were",
"identified.",
"Thirty-three",
"different",
"mutant",
"alleles",
"were",
"found,",
"including",
"point",
"mutations,",
"splice",
"junction",
"mutations,",
"deletions,",
"fusion",
"alleles",
"and",
"recombinant",
"alleles.",
"Eleven",
"novel",
"mutations",
"were",
"identified",
"in",
"these",
"patients:",
"R131L,",
"H255Q,",
"R285H,",
"S196P,",
"H311R,",
"c.330delA,",
"V398F,",
"F259L,",
"c.533delC,",
"Y304C",
"and",
"A190E.",
"Mutation",
"L444P",
"was",
"found",
"on",
"25",
"patient",
"alleles.",
"Southern",
"blots",
"and",
"direct",
"sequencing",
"demonstrated",
"that",
"mutation",
"L444P",
"occurred",
"alone",
"on",
"9",
"alleles,",
"with",
"E326K",
"on",
"one",
"allele",
"and",
"as",
"part",
"of",
"a",
"recombinant",
"allele",
"on",
"15",
"alleles.",
"There",
"were",
"no",
"homozygotes",
"for",
"point",
"mutation",
"L444P.",
"The",
"recombinant",
"alleles",
"that",
"included",
"L444P",
"resulted",
"from",
"either",
"reciprocal",
"recombination",
"or",
"gene",
"conversion",
"with",
"the",
"nearby",
"glucocerebrosidase",
"pseudogene,",
"and",
"seven",
"different",
"sites",
"of",
"recombination",
"were",
"identified.",
"Homozygosity",
"for",
"a",
"recombinant",
"allele",
"was",
"associated",
"with",
"early",
"lethality.",
"We",
"have",
"also",
"summarized",
"the",
"literature",
"describing",
"mutations",
"associated",
"with",
"type",
"2",
"disease,",
"and",
"list",
"50",
"different",
"mutations.",
"This",
"report",
"constitutes",
"the",
"most",
"comprehensive",
"molecular",
"study",
"to",
"date",
"of",
"type",
"2",
"Gaucher",
"disease,",
"and",
"it",
"demonstrates",
"that",
"there",
"is",
"significant",
"phenotypic",
"and",
"genotypic",
"heterogeneity",
"among",
"patients",
"with",
"type",
"2",
"Gaucher",
"disease.",
"Hum",
"Mutat",
"15:181-188,",
"2000.",
"Published",
"2000",
"Wiley-Liss,",
"Inc."
] | [
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
3,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. Gaucher disease, the most common lysosomal storage disorder, results from the inherited deficiency of the enzyme glucocerebrosidase. Three clinical types are recognized: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. Type 2 Gaucher disease, the rarest type, is progressive and fatal. We have performed molecular analyses of a cohort of 31 patients with type 2 Gaucher disease. The cases studied included fetuses presenting prenatally with hydrops fetalis, infants with the collodion baby phenotype, and infants diagnosed after several months of life. All 62 mutant glucocerebrosidase (GBA) alleles were identified. Thirty-three different mutant alleles were found, including point mutations, splice junction mutations, deletions, fusion alleles and recombinant alleles. Eleven novel mutations were identified in these patients: R131L , H255Q , R285H , S196P , H311R , c.330delA , V398F , F259L , c.533delC , Y304C and A190E . Mutation L444P was found on 25 patient alleles. Southern blots and direct sequencing demonstrated that mutation L444P occurred alone on 9 alleles, with E326K on one allele and as part of a recombinant allele on 15 alleles. There were no homozygotes for point mutation L444P . The recombinant alleles that included L444P glucocerebrosidase ( GBA ) alleles were identified. Thirty-three different mutant alleles were found, including point mutations, splice junction mutations, deletions, fusion alleles and recombinant alleles. Eleven novel mutations were identified in these patients: R131L, H255Q, R285H, S196P, H311R, c.330delA, V398F, F259L, c.533delC, Y304C and A190E. Mutation L444P was found on 25 patient alleles. Southern blots and direct sequencing demonstrated that mutation L444P occurred alone on 9 alleles, with E326K on one allele and as part of a recombinant allele on 15 alleles. There were no homozygotes for point mutation L444P. The recombinant alleles that included L444P resulted from either reciprocal recombination or gene conversion with the nearby glucocerebrosidase pseudogene, and seven different sites of recombination were identified. Homozygosity for a recombinant allele was associated with early lethality. We have also summarized the literature describing mutations associated with type 2 disease, and list 50 different mutations. This report constitutes the most comprehensive molecular study to date of type 2 Gaucher disease, and it demonstrates that there is significant phenotypic and genotypic heterogeneity among patients with type 2 Gaucher disease. Hum Mutat 15:181-188, 2000. Published 2000 Wiley-Liss, Inc. | [
2,
3351,
29673,
18474,
12924,
3825,
4127,
2359,
3527,
1922,
2132,
1956,
2601,
22,
4357,
21956,
2573,
18,
4357,
21956,
2573,
16,
1920,
2501,
3059,
12097,
7451,
4770,
16,
2274,
2037,
1920,
12911,
6179,
1927,
1920,
4113,
3351,
29673,
18474,
12924,
3825,
4127,
18,
2559,
2535,
3584,
2032,
6783,
30,
2601,
21,
16,
2447,
17,
7428,
10982,
31,
2601,
22,
16,
3939,
7428,
10982,
31,
1930,
2601,
23,
16,
25440,
7428,
10982,
18,
2601,
22,
4357,
21956,
2573,
16,
1920,
5844,
2156,
2601,
16,
1977,
7529,
1930,
11990,
18,
2038,
2162,
2593,
3272,
3247,
1927,
43,
4382,
1927,
3470,
2132,
1956,
2601,
22,
4357,
21956,
2573,
18,
1920,
2919,
3942,
3063,
16110,
8326,
10907,
1954,
1956,
3290,
2523,
5944,
1937,
16,
5969,
1956,
1920,
2674,
15799,
1916,
16099,
4629,
16,
1930,
5969,
5377,
2256,
2980,
3221,
1927,
3308,
18,
2136,
5374,
3606,
3351,
29673,
18474,
12924,
3825,
4127,
12,
7436,
1019,
13,
7096,
1985,
2899,
18,
9942,
17,
2559,
2413,
3606,
7096,
1985,
2435,
16,
2710,
3575,
3527,
16,
10708,
6910,
3527,
16,
10550,
16,
5289,
7096,
1930,
5752,
7096,
18,
14483,
4008,
3527,
1985,
2899,
1922,
2144,
2132,
30,
12041,
6800,
1024,
16,
4881,
7054,
1055,
16,
7261,
10025,
1023,
16,
4062,
10352,
1034,
16,
8170,
3242,
1005,
16,
45,
18,
18891,
16878,
1019,
16,
14307,
8364,
1038,
16,
11063,
7308,
1024,
16,
45,
18,
4522,
19494,
1938,
1030,
16,
67,
28124,
1030,
1930,
8080,
5124,
1021,
18,
3979,
16546,
6609,
1034,
1982,
2435,
1990,
2637,
2774,
7096,
18,
9257,
11305,
1930,
3083,
4754,
3161,
1988,
3979,
16546,
6609,
1034,
4807,
4298,
1990,
29,
7096,
16,
1956,
10968,
4684,
1040,
1990,
2340,
5465,
1930,
1966,
3131,
1927,
43,
5752,
5465,
1990,
2461,
7096,
18,
2276,
1985,
2239,
22686,
1958,
3575,
3979,
16546,
6609,
1034,
18,
1920,
5752,
7096,
1988,
3063,
16546,
6609,
1034,
3351,
29673,
18474,
12924,
3825,
4127,
12,
7436,
1019,
13,
7096,
1985,
2899,
18,
9942,
17,
2559,
2413,
3606,
7096,
1985,
2435,
16,
2710,
3575,
3527,
16,
10708,
6910,
3527,
16,
10550,
16,
5289,
7096,
1930,
5752,
7096,
18,
14483,
4008,
3527,
1985,
2899,
1922,
2144,
2132,
30,
12041,
6800,
1024,
16,
4881,
7054,
1055,
16,
7261,
10025,
1023,
16,
4062,
10352,
1034,
16,
8170,
3242,
1005,
16,
45,
18,
18891,
16878,
1019,
16,
14307,
8364,
1038,
16,
11063,
7308,
1024,
16,
45,
18,
4522,
19494,
1938,
1030,
16,
67,
28124,
1030,
1930,
8080,
5124,
1021,
18,
3979,
16546,
6609,
1034,
1982,
2435,
1990,
2637,
2774,
7096,
18,
9257,
11305,
1930,
3083,
4754,
3161,
1988,
3979,
16546,
6609,
1034,
4807,
4298,
1990,
29,
7096,
16,
1956,
10968,
4684,
1040,
1990,
2340,
5465,
1930,
1966,
3131,
1927,
43,
5752,
5465,
1990,
2461,
7096,
18,
2276,
1985,
2239,
22686,
1958,
3575,
3979,
16546,
6609,
1034,
18,
1920,
5752,
7096,
1988,
3063,
16546,
6609,
1034,
4306,
2037,
3108,
13462,
7827,
2014,
2359,
7309,
1956,
1920,
15485,
3351,
29673,
18474,
12924,
3825,
4127,
11520,
14687,
16,
1930,
5260,
2413,
3402,
1927,
7827,
1985,
2899,
18,
29992,
1958,
43,
5752,
5465,
1982,
2458,
1956,
3120,
15400,
18,
2038,
2162,
2222,
8440,
1920,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
1,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
3,
4,
4,
1,
2,
2,
2,
2,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
10441582 | [
"A",
"second",
"gene",
"for",
"autosomal",
"dominant",
"Möbius",
"syndrome",
"is",
"localized",
"to",
"chromosome",
"10q,",
"in",
"a",
"Dutch",
"family.",
"Möbius",
"syndrome",
"(MIM",
"157900)",
"consists",
"of",
"a",
"congenital",
"paresis",
"or",
"paralysis",
"of",
"the",
"VIIth",
"(facial)",
"cranial",
"nerve,",
"frequently",
"accompanied",
"by",
"dysfunction",
"of",
"other",
"cranial",
"nerves.",
"The",
"abducens",
"nerve",
"is",
"typically",
"affected,",
"and",
"often,",
"also,",
"the",
"hypoglossal",
"nerve.",
"In",
"addition,",
"orofacial",
"and",
"limb",
"malformations,",
"defects",
"of",
"the",
"musculoskeletal",
"system,",
"and",
"mental",
"retardation",
"are",
"seen",
"in",
"patients",
"with",
"Möbius",
"syndrome.",
"Most",
"cases",
"are",
"sporadic,",
"but",
"familial",
"recurrence",
"can",
"occur.",
"Different",
"modes",
"of",
"inheritance",
"are",
"suggested",
"by",
"different",
"pedigrees.",
"Genetic",
"heterogeneity",
"of",
"Möbius",
"syndrome",
"has",
"been",
"suggested",
"by",
"cytogenetic",
"studies",
"and",
"linkage",
"analysis.",
"Previously,",
"we",
"identified",
"a",
"locus",
"on",
"chromosome",
"3q21-22,",
"in",
"a",
"large",
"Dutch",
"family",
"with",
"Möbius",
"syndrome",
"consisting",
"essentially",
"of",
"autosomal",
"dominant",
"asymmetric",
"bilateral",
"facial",
"paresis.",
"Here",
"we",
"report",
"linkage",
"analysis",
"in",
"a",
"second",
"large",
"Dutch",
"family",
"with",
"autosomal",
"dominant",
"inherited",
"facial",
"paresis.",
"After",
"exclusion",
"of",
">90%",
"of",
"the",
"genome,",
"we",
"identified",
"the",
"locus",
"on",
"the",
"long",
"arm",
"of",
"chromosome",
"10",
"in",
"this",
"family,",
"demonstrating",
"genetic",
"heterogeneity",
"of",
"this",
"condition.",
"The",
"reduced",
"penetrance",
"suggests",
"that",
"at",
"least",
"some",
"of",
"the",
"sporadic",
"cases",
"might",
"be",
"familial."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A second gene for autosomal dominant Möbius syndrome is localized to chromosome 10q, in a Dutch family. Möbius syndrome (MIM 157900) consists of a congenital paresis or paralysis of the VIIth (facial) cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is typically affected, and often, also, the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system, and mental retardation are seen in patients with Möbius syndrome. Most cases are sporadic, but familial recurrence can occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Möbius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21-22, in a large Dutch family with Möbius syndrome consisting essentially of autosomal dominant asymmetric bilateral facial paresis. Here we report linkage analysis in a second large Dutch family with autosomal dominant inherited facial paresis. After exclusion of >90% of the genome, we identified the locus on the long arm of chromosome 10 in this family, demonstrating genetic heterogeneity of this condition. The reduced penetrance suggests that at least some of the sporadic cases might be familial. | [
2,
43,
2812,
2359,
1958,
13027,
6379,
5340,
11519,
4741,
1977,
6579,
1942,
5597,
2119,
1055,
16,
1922,
43,
15150,
3416,
18,
5340,
11519,
4741,
12,
6571,
14358,
5124,
1008,
13,
7543,
1927,
43,
9901,
2096,
2600,
2014,
18973,
1927,
1920,
16852,
1963,
12,
9567,
13,
13598,
5507,
16,
5467,
7936,
2007,
5273,
1927,
2303,
13598,
12014,
18,
1920,
11754,
3005,
3355,
5507,
1977,
5745,
4218,
16,
1930,
3868,
16,
2222,
16,
1920,
14395,
4365,
3117,
1923,
5507,
18,
1922,
2459,
16,
25027,
18703,
1930,
7755,
17360,
16,
6007,
1927,
1920,
15322,
2433,
16,
1930,
5018,
16342,
2032,
3945,
1922,
2132,
1956,
5340,
11519,
4741,
18,
2501,
2919,
2032,
13088,
16,
2308,
11444,
6339,
2112,
4704,
18,
2413,
9606,
1927,
15762,
2032,
3978,
2007,
2413,
22336,
1036,
18,
3299,
6808,
1927,
5340,
11519,
4741,
2258,
2252,
3978,
2007,
18486,
2351,
1930,
8611,
2333,
18,
3024,
16,
2038,
2899,
43,
6730,
1990,
5597,
23,
23470,
1009,
17,
2950,
16,
1922,
43,
3103,
15150,
3416,
1956,
5340,
11519,
4741,
7600,
10163,
1927,
13027,
6379,
11474,
7787,
9567,
2096,
2600,
18,
3410,
2038,
3809,
8611,
2333,
1922,
43,
2812,
3103,
15150,
3416,
1956,
13027,
6379,
12911,
9567,
2096,
2600,
18,
2256,
7901,
1927,
34,
3865,
9,
1927,
1920,
3843,
16,
2038,
2899,
1920,
6730,
1990,
1920,
2815,
6011,
1927,
5597,
2119,
1922,
2052,
3416,
16,
7530,
3299,
6808,
1927,
2052,
2625,
18,
1920,
3028,
22035,
4015,
1988,
2019,
3464,
2673,
1927,
1920,
13088,
2919,
3284,
1998,
11444,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1301957 | [
"Molecular",
"analysis",
"of",
"neurofibromatosis",
"type",
"1",
" ",
"mutations.",
"We",
"have",
"examined",
"a",
"panel",
"of",
"115",
"unrelated",
"NF1",
" ",
"individuals",
"for",
"mutation",
"in",
"the",
"3'",
"region",
"of",
"the",
"NF1",
" ",
"gene,",
"using",
"Southern",
"blotting",
"and",
"polymerase",
"chain",
"reaction",
"amplification",
"of",
"exons",
"followed",
"by",
"single-strand",
"conformation",
"polymorphism",
"(SSCP)",
"analysis.",
"We",
"found",
"only",
"2",
"unequivocal",
"mutations:",
"a",
"571",
"bp",
"deletion",
"which",
"removed",
"exon",
"6",
"and",
"resulted",
"in",
"a",
"frameshift",
"in",
"exon",
"7,",
"and",
"a",
"2",
"bp",
"deletion",
"in",
"exon",
"1.",
"A",
"third",
"sequence",
"variation",
"detected",
"by",
"SSCP",
"was",
"predicted",
"to",
"cause",
"a",
"lysine-arginine",
"substitution",
"in",
"exon",
"6.",
"This",
"is",
"a",
"conservative",
"change,",
"and",
"since",
"the",
"affected",
"individual",
"is",
"a",
"new",
"mutation",
"whose",
"parents",
"are",
"not",
"available,",
"we",
"cannot",
"be",
"sure",
"of",
"its",
"biological",
"significance.",
"We",
"detected",
"mutations",
"in",
"at",
"most",
"3%",
"of",
"individuals,",
"from",
"an",
"analysis",
"which",
"covered",
"17%",
"of",
"the",
"coding",
"sequence",
"by",
"SSCP",
"and",
"a",
"larger",
"region",
"by",
"Southern",
"blotting.",
"This",
"relative",
"failure",
"to",
"detect",
"mutations",
"accords",
"with",
"the",
"experience",
"of",
"others.",
"Even",
"allowing",
"for",
"the",
"incomplete",
"sensitivity",
"of",
"the",
"methods",
"used,",
"the",
"results",
"suggest",
"that",
"the",
"majority",
"of",
"NF1",
" ",
"mutations",
"lie",
"elsewhere",
"in",
"the",
"coding",
"sequence",
"or",
"outside",
"it."
] | [
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Molecular analysis of neurofibromatosis type 1 mutations. We have examined a panel of 115 unrelated NF1 individuals for mutation in the 3' region of the NF1 gene, using Southern blotting and polymerase chain reaction amplification of exons followed by single-strand conformation polymorphism (SSCP) analysis. We found only 2 unequivocal mutations: a 571 bp deletion which removed exon 6 and resulted in a frameshift in exon 7, and a 2 bp deletion in exon 1. A third sequence variation detected by SSCP was predicted to cause a lysine-arginine substitution in exon 6. This is a conservative change, and since the affected individual is a new mutation whose parents are not available, we cannot be sure of its biological significance. We detected mutations in at most 3% of individuals, from an analysis which covered 17% of the coding sequence by SSCP and a larger region by Southern blotting. This relative failure to detect mutations accords with the experience of others. Even allowing for the incomplete sensitivity of the methods used, the results suggest that the majority of NF1 mutations lie elsewhere in the coding sequence or outside it. | [
2,
3272,
2333,
1927,
26311,
11299,
2601,
21,
3527,
18,
2038,
2162,
3572,
43,
4812,
1927,
10709,
10295,
19387,
3445,
1958,
3979,
1922,
1920,
23,
11,
3031,
1927,
1920,
19387,
2359,
16,
2193,
9257,
8390,
1930,
6479,
4659,
3227,
6584,
1927,
10419,
3489,
2007,
2957,
17,
5984,
7748,
8218,
12,
13061,
1034,
13,
2333,
18,
2038,
2435,
2444,
22,
23558,
5000,
3527,
30,
43,
4786,
1009,
4149,
5541,
2154,
5231,
7049,
26,
1930,
4306,
1922,
43,
21848,
1922,
7049,
27,
16,
1930,
43,
22,
4149,
5541,
1922,
7049,
21,
18,
43,
4563,
3244,
4516,
3330,
2007,
13061,
1034,
1982,
4396,
1942,
3936,
43,
9082,
17,
9732,
6636,
1922,
7049,
26,
18,
2052,
1977,
43,
11375,
3185,
16,
1930,
3328,
1920,
4218,
2725,
1977,
43,
2814,
3979,
6098,
5853,
2032,
2084,
3322,
16,
2038,
5156,
1998,
16320,
1927,
2496,
3933,
4550,
18,
2038,
3330,
3527,
1922,
2019,
2501,
23,
9,
1927,
3445,
16,
2037,
1925,
2333,
2154,
8710,
2752,
9,
1927,
1920,
5804,
3244,
2007,
13061,
1034,
1930,
43,
4327,
3031,
2007,
9257,
8390,
18,
2052,
3338,
4574,
1942,
4277,
3527,
23422,
1036,
1956,
1920,
4848,
1927,
4991,
18,
3385,
7201,
1958,
1920,
9876,
3802,
1927,
1920,
2860,
2251,
16,
1920,
2274,
3220,
1988,
1920,
4827,
1927,
19387,
3527,
14958,
10132,
1922,
1920,
5804,
3244,
2014,
7008,
2176,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
22434506 | [
"Large-scale",
"objective",
"phenotyping",
"of",
"3D",
"facial",
"morphology.",
"Abnormal",
"phenotypes",
"have",
"played",
"significant",
"roles",
"in",
"the",
"discovery",
"of",
"gene",
"function,",
"but",
"organized",
"collection",
"of",
"phenotype",
"data",
"has",
"been",
"overshadowed",
"by",
"developments",
"in",
"sequencing",
"technology.",
"In",
"order",
"to",
"study",
"phenotypes",
"systematically,",
"large-scale",
"projects",
"with",
"standardized",
"objective",
"assessment",
"across",
"populations",
"are",
"considered",
"necessary.",
"The",
"report",
"of",
"the",
"2006",
"Human",
"Variome",
"Project",
"meeting",
"(Cotton",
"et",
"al,",
"2007)",
"recommended",
"documentation",
"of",
"phenotypes",
"through",
"electronic",
"means",
"by",
"collaborative",
"groups",
"of",
"computational",
"scientists",
"and",
"clinicians",
"using",
"standard,",
"structured",
"descriptions",
"of",
"disease-specific",
"phenotypes.",
"In",
"this",
"report,",
"we",
"describe",
"progress",
"over",
"the",
"past",
"decade",
"in",
"three-dimensional",
"(3D)",
"digital",
"imaging",
"and",
"shape",
"analysis",
"of",
"the",
"face,",
"and",
"future",
"prospects",
"for",
"large-scale",
"facial",
"phenotyping.",
"Illustrative",
"examples",
"are",
"given",
"throughout",
"using",
"a",
"collection",
"of",
"1,107",
"3D",
"face",
"images",
"of",
"healthy",
"controls",
"and",
"individuals",
"with",
"a",
"range",
"of",
"genetic",
"conditions",
"involving",
"facial",
"dysmorphism."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Large-scale objective phenotyping of 3D facial morphology. Abnormal phenotypes have played significant roles in the discovery of gene function, but organized collection of phenotype data has been overshadowed by developments in sequencing technology. In order to study phenotypes systematically, large-scale projects with standardized objective assessment across populations are considered necessary. The report of the 2006 Human Variome Project meeting (Cotton et al, 2007) recommended documentation of phenotypes through electronic means by collaborative groups of computational scientists and clinicians using standard, structured descriptions of disease-specific phenotypes. In this report, we describe progress over the past decade in three-dimensional (3D) digital imaging and shape analysis of the face, and future prospects for large-scale facial phenotyping. Illustrative examples are given throughout using a collection of 1,107 3D face images of healthy controls and individuals with a range of genetic conditions involving facial dysmorphism. | [
2,
3103,
17,
3536,
4470,
24485,
1927,
5050,
9567,
6076,
18,
4552,
6568,
2162,
11895,
2228,
5456,
1922,
1920,
7139,
1927,
2359,
2347,
16,
2308,
11275,
4957,
1927,
4629,
2230,
2258,
2252,
17774,
2722,
22389,
2172,
1007,
2007,
15411,
1922,
4754,
5397,
18,
1922,
3238,
1942,
2161,
6568,
11073,
16,
3103,
17,
3536,
11662,
1956,
7496,
4470,
4076,
3436,
4098,
2032,
3311,
4680,
18,
1920,
3809,
1927,
1920,
3956,
2616,
2309,
2225,
5539,
8957,
12,
14970,
2140,
1969,
16,
3826,
13,
6198,
14924,
1927,
6568,
2596,
7703,
4457,
2007,
13961,
2671,
1927,
8216,
13948,
1930,
8575,
2193,
2970,
16,
9217,
14947,
1927,
2573,
17,
2487,
6568,
18,
1922,
2052,
3809,
16,
2038,
5993,
4782,
2338,
1920,
5375,
10468,
1922,
2559,
17,
6477,
12,
5050,
13,
8225,
3755,
1930,
5989,
2333,
1927,
1920,
6171,
16,
1930,
4115,
29565,
1958,
3103,
17,
3536,
9567,
24485,
18,
5502,
2178,
7604,
2032,
3258,
5264,
2193,
43,
4957,
1927,
21,
16,
9176,
5050,
6171,
3800,
1927,
4097,
3562,
1930,
3445,
1956,
43,
3109,
1927,
3299,
2961,
5884,
9567,
26906,
28119,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
10874330 | [
"A",
"novel",
"mutation",
"(",
"1320InsT",
")",
"identified",
"in",
"two",
"Argentine",
"families",
"with",
"variegate",
"porphyria."
] | [
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A novel mutation ( 1320InsT ) identified in two Argentine families with variegate porphyria. | [
2,
43,
4008,
3979,
12,
11824,
1008,
2925,
1031,
13,
2899,
1922,
2288,
23015,
2912,
5767,
1956,
2309,
11253,
2057,
17376,
3553,
2126,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1301950 | [
"Detection",
"of",
"sequence",
"variants",
"in",
"the",
"gene",
"for",
"human",
"type",
"II",
"procollagen",
" ",
"(",
"COL2A1",
")",
"by",
"direct",
"sequencing",
"of",
"polymerase",
"chain",
"reaction-amplified",
"genomic",
"DNA.",
"The",
"direct",
"sequencing",
"of",
"the",
"human",
"type",
"II",
"procollagen",
"(",
"COL2A1",
"type",
"II",
"procollagen",
" ",
"(COL2A1)",
"gene",
"from",
"polymerase",
"chain",
"reaction",
"(PCR)-amplified",
"genomic",
"DNA",
"is",
"described.",
"Thirty-two",
"regions",
"of",
"the",
"COL2A1",
"gene",
"were",
"asymmetrically",
"amplified",
"with",
"intron",
"primers",
"which",
"were",
"specifically",
"chosen",
"to",
"amplify",
"a",
"region",
"spanning",
"500",
"to",
"800",
"bp",
"of",
"sequence",
"encoding",
"one",
"or",
"more",
"exons",
"and",
"their",
"accompanying",
"intervening",
"sequences.",
"Primers",
"for",
"dideoxynucleotide",
"sequencing",
"of",
"the",
"PCR",
"products",
"were",
"then",
"designed",
"to",
"provide",
"complete",
"exon",
"sequence",
"information",
"and",
"to",
"insure",
"that",
"intron:exon",
"splice",
"junction",
"sequence",
"data",
"would",
"be",
"obtained.",
"Amplification",
"and",
"sequencing",
"reactions",
"were",
"performed",
"on",
"an",
"automated",
"workstation",
"to",
"facilitate",
"the",
"handling",
"of",
"multiple",
"DNA",
"templates.",
"The",
"procedure",
"allowed",
"efficient",
"sequencing",
"of",
"over",
"25,000",
"bp",
"of",
"each",
"allele",
"of",
"the",
"COL2A1",
"gene",
"per",
"diploid",
"genome.",
"We",
"used",
"this",
"method",
"for",
"the",
"comparative",
"analyses",
"of",
"COL2A1",
" ",
"sequences",
"in",
"DNA",
"isolated",
"from",
"the",
"blood",
"of",
"42",
"unrelated",
"individuals",
"and",
"we",
"identified",
"21",
"neutral",
"sequence",
"variants",
"in",
"the",
"gene.",
"The",
"sequence",
"variations",
"were",
"confirmed",
"by",
"independent",
"assays,",
"including",
"restriction",
"enzyme",
"digestion.",
"The",
"sequence",
"variants",
"described",
"here",
"will",
"be",
"important",
"for",
"identifying",
"haplotypes",
"of",
"the",
"type",
"II",
"procollagen",
" ",
"gene",
"that",
"will",
"be",
"useful",
"in",
"defining",
"a",
"genetic",
"etiology",
"for",
"diseases",
"of",
"cartilaginous",
"tissues."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Detection of sequence variants in the gene for human type II procollagen ( COL2A1 ) by direct sequencing of polymerase chain reaction-amplified genomic DNA. The direct sequencing of the human type II procollagen ( COL2A1 type II procollagen (COL2A1) gene from polymerase chain reaction (PCR)-amplified genomic DNA is described. Thirty-two regions of the COL2A1 gene were asymmetrically amplified with intron primers which were specifically chosen to amplify a region spanning 500 to 800 bp of sequence encoding one or more exons and their accompanying intervening sequences. Primers for dideoxynucleotide sequencing of the PCR products were then designed to provide complete exon sequence information and to insure that intron:exon splice junction sequence data would be obtained. Amplification and sequencing reactions were performed on an automated workstation to facilitate the handling of multiple DNA templates. The procedure allowed efficient sequencing of over 25,000 bp of each allele of the COL2A1 gene per diploid genome. We used this method for the comparative analyses of COL2A1 sequences in DNA isolated from the blood of 42 unrelated individuals and we identified 21 neutral sequence variants in the gene. The sequence variations were confirmed by independent assays, including restriction enzyme digestion. The sequence variants described here will be important for identifying haplotypes of the type II procollagen gene that will be useful in defining a genetic etiology for diseases of cartilaginous tissues. | [
2,
3805,
1927,
3244,
4936,
1922,
1920,
2359,
1958,
2616,
2601,
2890,
9823,
30431,
12,
2503,
5896,
1009,
13,
2007,
3083,
4754,
1927,
6479,
4659,
3227,
17,
7006,
4935,
2678,
18,
1920,
3083,
4754,
1927,
1920,
2616,
2601,
2890,
9823,
30431,
12,
2503,
5896,
1009,
2601,
2890,
9823,
30431,
12,
2503,
5896,
1009,
13,
2359,
2037,
6479,
4659,
3227,
12,
3343,
13,
17,
7006,
4935,
2678,
1977,
2910,
18,
9942,
17,
2288,
3451,
1927,
1920,
2503,
5896,
1009,
2359,
1985,
27184,
1954,
7006,
1956,
10444,
5696,
2154,
1985,
4475,
6724,
1942,
14528,
43,
3031,
13346,
4599,
1942,
9658,
4149,
1927,
3244,
5797,
2340,
2014,
2253,
10419,
1930,
2310,
15252,
23241,
3709,
18,
5696,
1958,
2811,
1021,
7221,
1022,
15274,
4754,
1927,
1920,
3343,
4461,
1985,
2759,
4609,
1942,
3394,
4080,
7049,
3244,
2988,
1930,
1942,
7697,
1936,
1988,
10444,
30,
7049,
10708,
6910,
3244,
2230,
2962,
1998,
2926,
18,
6584,
1930,
4754,
5298,
1985,
2593,
1990,
1925,
9210,
10997,
4926,
1942,
6628,
1920,
12361,
1927,
3137,
2678,
14559,
18,
1920,
4360,
5563,
5807,
4754,
1927,
2338,
2637,
16,
3240,
4149,
1927,
2362,
5465,
1927,
1920,
2503,
5896,
1009,
2359,
2079,
16613,
3843,
18,
2038,
2251,
2052,
2417,
1958,
1920,
8255,
3247,
1927,
2503,
5896,
1009,
3709,
1922,
2678,
3937,
2037,
1920,
2877,
1927,
3858,
10295,
3445,
1930,
2038,
2899,
2900,
5459,
3244,
4936,
1922,
1920,
2359,
18,
1920,
3244,
6740,
1985,
3982,
2007,
3484,
4614,
16,
2710,
7587,
4113,
9379,
18,
1920,
3244,
4936,
2910,
3410,
2832,
1998,
2715,
1958,
6993,
12149,
1927,
1920,
2601,
2890,
9823,
30431,
2359,
1988,
2832,
1998,
4707,
1922,
11266,
43,
3299,
10383,
1958,
3902,
1927,
8301,
29674,
3878,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
18381613 | [
"A",
"multicenter",
"study",
"on",
"the",
"prevalence",
"and",
"spectrum",
"of",
"mutations",
"in",
"the",
"otoferlin",
"gene",
"(",
"OTOF",
"otoferlin",
"gene",
" ",
"(OTOF)",
"in",
"subjects",
"with",
"nonsyndromic",
"hearing",
"impairment",
"and",
"auditory",
"neuropathy.",
"Autosomal",
"recessive",
"nonsyndromic",
"hearing",
"impairment",
"(NSHI)",
"is",
"a",
"heterogeneous",
"condition,",
"for",
"which",
"53",
"genetic",
"loci",
"have",
"been",
"reported,",
"and",
"29",
"genes",
"have",
"been",
"identified",
"to",
"date.",
"One",
"of",
"these,",
"OTOF,",
"encodes",
"otoferlin,",
"a",
"membrane-anchored",
"calcium-binding",
"protein",
"that",
"plays",
"a",
"role",
"in",
"the",
"exocytosis",
"of",
"synaptic",
"vesicles",
"at",
"the",
"auditory",
"inner",
"hair",
"cell",
"ribbon",
"synapse.",
"We",
"have",
"investigated",
"the",
"prevalence",
"and",
"spectrum",
"of",
"deafness-causing",
"mutations",
"in",
"the",
"OTOF",
" ",
"gene.",
"Cohorts",
"of",
"708",
"Spanish,",
"83",
"Colombian,",
"and",
"30",
"Argentinean",
"unrelated",
"subjects",
"with",
"autosomal",
"recessive",
"NSHI",
"were",
"screened",
"for",
"the",
"common",
"p.Gln829X",
" ",
"mutation.",
"In",
"compound",
"heterozygotes,",
"the",
"second",
"mutant",
"allele",
"was",
"identified",
"by",
"DNA",
"sequencing.",
"In",
"total,",
"23",
"Spanish,",
"two",
"Colombian",
"and",
"two",
"Argentinean",
"subjects",
"were",
"shown",
"to",
"carry",
"two",
"mutant",
"alleles",
"of",
"OTOF.",
"Of",
"these,",
"one",
"Colombian",
"and",
"13",
"Spanish",
"subjects",
"presented",
"with",
"auditory",
"neuropathy.",
"In",
"addition,",
"a",
"cohort",
"of",
"20",
"unrelated",
"subjects",
"with",
"a",
"diagnosis",
"of",
"auditory",
"neuropathy,",
"from",
"several",
"countries,",
"was",
"screened",
"for",
"mutations",
"in",
"OTOF",
"by",
"DNA",
"sequencing.",
"A",
"total",
"of",
"11",
"of",
"these",
"subjects",
"were",
"shown",
"to",
"carry",
"two",
"mutant",
"alleles",
"of",
"OTOF.",
"In",
"total,",
"18",
"pathogenic",
"and",
"four",
"neutral",
"novel",
"alleles",
"of",
"the",
"OTOF",
"OTOF",
".",
"In",
"total,",
"18",
"pathogenic",
"and",
"four",
"neutral",
"novel",
"alleles",
"of",
"the",
"OTOF",
"gene",
"were",
"identified.",
"Haplotype",
"analysis",
"for",
"markers",
"close",
"to",
"OTOF",
" ",
"suggests",
"a",
"common",
"founder",
"for",
"the",
"novel",
"c.2905_2923delinsCTCCGAGCGCA",
" ",
"mutation,",
"frequently",
"found",
"in",
"Argentina.",
"Our",
"results",
"confirm",
"that",
"mutation",
"of",
"the",
"OTOF",
" ",
"gene",
"correlates",
"with",
"a",
"phenotype",
"of",
"prelingual,",
"profound",
"NSHI,",
"and",
"indicate",
"that",
"OTOF",
" ",
"mutations",
"are",
"a",
"major",
"cause",
"of",
"inherited",
"auditory",
"neuropathy."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene ( OTOF otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy. Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF OTOF . In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy. | [
2,
43,
14620,
2161,
1990,
1920,
4077,
1930,
5648,
1927,
3527,
1922,
1920,
7608,
28079,
7782,
2359,
12,
7608,
4199,
7608,
28079,
7782,
2359,
12,
7608,
4199,
13,
1922,
3297,
1956,
23428,
3883,
3264,
8512,
6159,
1930,
8401,
13177,
18,
13027,
13992,
23428,
3883,
3264,
8512,
6159,
12,
4246,
7969,
13,
1977,
43,
8538,
2625,
16,
1958,
2154,
4522,
3299,
6971,
2162,
2252,
2568,
16,
1930,
3230,
2628,
2162,
2252,
2899,
1942,
5699,
18,
2340,
1927,
2144,
16,
7608,
4199,
16,
9937,
7608,
28079,
7782,
16,
43,
3260,
17,
17199,
5016,
17,
2743,
2213,
1988,
5705,
43,
2770,
1922,
1920,
18904,
1927,
6251,
8319,
2019,
1920,
8401,
6671,
7018,
2024,
25149,
13103,
18,
2038,
2162,
3845,
1920,
4077,
1930,
5648,
1927,
25371,
17,
7538,
3527,
1922,
1920,
7608,
4199,
2359,
18,
8509,
1927,
3895,
1025,
13289,
16,
5893,
27676,
1022,
16,
1930,
2627,
23015,
9707,
1022,
10295,
3297,
1956,
13027,
13992,
4246,
7969,
1985,
8582,
1958,
1920,
3059,
58,
18,
15236,
11715,
1026,
1039,
3979,
18,
1922,
3547,
22910,
16,
1920,
2812,
3606,
5465,
1982,
2899,
2007,
2678,
4754,
18,
1922,
2698,
16,
3020,
13289,
16,
2288,
27676,
1022,
1930,
2288,
23015,
9707,
1022,
3297,
1985,
2522,
1942,
9875,
2288,
3606,
7096,
1927,
7608,
4199,
18,
1927,
2144,
16,
2340,
27676,
1022,
1930,
2590,
13289,
3297,
3549,
1956,
8401,
13177,
18,
1922,
2459,
16,
43,
4382,
1927,
2036,
10295,
3297,
1956,
43,
3574,
1927,
8401,
13177,
16,
2037,
2980,
5085,
16,
1982,
8582,
1958,
3527,
1922,
7608,
4199,
2007,
2678,
4754,
18,
43,
2698,
1927,
2513,
1927,
2144,
3297,
1985,
2522,
1942,
9875,
2288,
3606,
7096,
1927,
7608,
4199,
18,
1922,
2698,
16,
2654,
8070,
1930,
3006,
5459,
4008,
7096,
1927,
1920,
7608,
4199,
7608,
4199,
18,
1922,
2698,
16,
2654,
8070,
1930,
3006,
5459,
4008,
7096,
1927,
1920,
7608,
4199,
2359,
1985,
2899,
18,
10949,
2333,
1958,
4432,
5428,
1942,
7608,
4199,
4015,
43,
3059,
21350,
1958,
1920,
4008,
45,
18,
19029,
1015,
41,
23376,
19494,
11136,
12709,
6916,
1030,
10736,
1030,
29315,
3979,
16,
5467,
2435,
1922,
25431,
18,
2342,
2274,
4763,
1988,
3979,
1927,
1920,
7608,
4199,
2359,
8706,
1956,
43,
4629,
1927,
2097,
3961,
2224,
16,
11098,
4246,
7969,
16,
1930,
3579,
1988,
7608,
4199,
3527,
2032,
43,
3044,
3936,
1927,
12911,
8401,
13177,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
16773577 | [
"Familial",
"osteoarthritis",
"of",
"the",
"hip",
"joint",
"associated",
"with",
"acetabular",
"dysplasia",
"maps",
"to",
"chromosome",
"13q.",
"Genetic",
"factors",
"have",
"been",
"implicated",
"in",
"osteoarthritis",
"(OA),",
"particularly",
"in",
"OA",
"of",
"the",
"hip",
"joint",
"(hip",
"OA).",
"Several",
"instances",
"of",
"familial",
"hip",
"OA",
"that",
"show",
"distinctive",
"modes",
"of",
"inheritance",
"but",
"that",
"differ",
"from",
"chondrodysplasia",
"have",
"been",
"reported.",
"Here,",
"we",
"report",
"the",
"characterization",
"of",
"a",
"large",
"Japanese",
"family",
"with",
"an",
"inherited",
"disease",
"of",
"the",
"hip",
"that",
"is",
"indistinguishable",
"from",
"common",
"hip",
"OA,",
"as",
"evidenced",
"by",
"clinical",
"symptoms",
"and",
"radiographs",
"of",
"the",
"joint.",
"This",
"family",
"contained",
"eight",
"patients",
"in",
"4",
"generations.",
"Affected",
"individuals",
"develop",
"pain",
"in",
"the",
"hip",
"joint",
"during",
"adolescence,",
"and",
"the",
"disease",
"progresses",
"to",
"severe",
"crippling",
"before",
"age",
"60",
"years.",
"Patients",
"generally",
"are",
"in",
"good",
"health,",
"height",
"is",
"not",
"reduced,",
"and",
"there",
"is",
"no",
"extraskeletal",
"involvement",
"suggestive",
"of",
"chondrodysplasia.",
"The",
"skeletal",
"change",
"is",
"bilateral",
"acetabular",
"dysplasia",
"followed",
"by",
"OA,",
"which",
"occurs",
"after",
"age",
"approximately",
"40",
"years",
"and",
"is",
"indistinguishable",
"from",
"idiopathic",
"nonfamilial",
"dysplastic",
"hip",
"OA.",
"This",
"trait",
"shows",
"autosomal",
"dominant",
"inheritance,",
"with",
"a",
"considerably",
"consistent",
"phenotype.",
"Genomewide",
"screening",
"revealed",
"linkage",
"at",
"chromosome",
"13q22,",
"and",
"haplotype",
"analysis",
"narrowed",
"the",
"locus",
"to",
"a",
"6.0-cM",
"interval",
"between",
"markers",
"D13S1296",
"and",
"D13S162,",
"with",
"a",
"maximal",
"multipoint",
"LOD",
"score",
"of",
"3.57.",
"The",
"family",
"described",
"here",
"represents",
"a",
"novel",
"genetic",
"entity",
"as",
"a",
"monogenic",
"form",
"of",
"hip",
"OA.",
"Its",
"further",
"characterization",
"can",
"aid",
"in",
"elucidating",
"the",
"etiology",
"and",
"pathogenesis",
"of",
"a",
"common",
"idiopathic",
"form",
"of",
"OA."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Familial osteoarthritis of the hip joint associated with acetabular dysplasia maps to chromosome 13q. Genetic factors have been implicated in osteoarthritis (OA), particularly in OA of the hip joint (hip OA). Several instances of familial hip OA that show distinctive modes of inheritance but that differ from chondrodysplasia have been reported. Here, we report the characterization of a large Japanese family with an inherited disease of the hip that is indistinguishable from common hip OA, as evidenced by clinical symptoms and radiographs of the joint. This family contained eight patients in 4 generations. Affected individuals develop pain in the hip joint during adolescence, and the disease progresses to severe crippling before age 60 years. Patients generally are in good health, height is not reduced, and there is no extraskeletal involvement suggestive of chondrodysplasia. The skeletal change is bilateral acetabular dysplasia followed by OA, which occurs after age approximately 40 years and is indistinguishable from idiopathic nonfamilial dysplastic hip OA. This trait shows autosomal dominant inheritance, with a considerably consistent phenotype. Genomewide screening revealed linkage at chromosome 13q22, and haplotype analysis narrowed the locus to a 6.0-cM interval between markers D13S1296 and D13S162, with a maximal multipoint LOD score of 3.57. The family described here represents a novel genetic entity as a monogenic form of hip OA. Its further characterization can aid in elucidating the etiology and pathogenesis of a common idiopathic form of OA. | [
2,
11444,
15027,
1927,
1920,
7679,
6047,
2458,
1956,
25767,
14095,
7422,
1942,
5597,
2590,
1055,
18,
3299,
2790,
2162,
2252,
6835,
1922,
15027,
12,
8965,
13,
16,
4443,
1922,
8965,
1927,
1920,
7679,
6047,
12,
7679,
8965,
13,
18,
2980,
12421,
1927,
11444,
7679,
8965,
1988,
2146,
15308,
9606,
1927,
15762,
2308,
1988,
2129,
2037,
22480,
14458,
3508,
24605,
2126,
2162,
2252,
2568,
18,
3410,
16,
2038,
3809,
1920,
7285,
1927,
43,
3103,
10405,
3416,
1956,
1925,
12911,
2573,
1927,
1920,
7679,
1988,
1977,
16586,
2037,
3059,
7679,
8965,
16,
1966,
11400,
2007,
2535,
3601,
1930,
15104,
1927,
1920,
6047,
18,
2052,
3416,
5543,
5066,
2132,
1922,
24,
12497,
18,
4218,
3445,
2392,
3594,
1922,
1920,
7679,
6047,
2409,
11845,
16,
1930,
1920,
2573,
20859,
1942,
4010,
3828,
9434,
3961,
3119,
2632,
3276,
2739,
18,
2132,
4933,
2032,
1922,
4227,
2436,
16,
6178,
1977,
2084,
3028,
16,
1930,
2276,
1977,
2239,
8324,
13254,
6092,
5668,
12855,
1927,
22480,
14458,
3508,
24605,
2126,
18,
1920,
7345,
3185,
1977,
7787,
25767,
14095,
3489,
2007,
8965,
16,
2154,
5110,
2256,
2632,
3993,
3040,
2739,
1930,
1977,
16586,
2037,
13513,
19136,
23767,
1923,
27546,
7679,
8965,
18,
2052,
8823,
3661,
13027,
6379,
15762,
16,
1956,
43,
9760,
3499,
4629,
18,
3843,
7641,
4449,
3404,
8611,
2019,
5597,
2590,
23470,
1028,
16,
1930,
10949,
2333,
8400,
1919,
1920,
6730,
1942,
43,
26,
18,
20,
17,
3195,
4979,
2192,
4432,
8524,
1010,
12030,
4539,
1016,
1930,
8524,
1010,
12030,
8166,
16,
1956,
43,
7275,
20677,
4418,
15187,
3593,
1927,
23,
18,
4786,
18,
1920,
3416,
2910,
3410,
4972,
43,
4008,
3299,
14866,
1966,
43,
8914,
11216,
2386,
1927,
7679,
8965,
18,
2496,
2520,
7285,
2112,
8379,
1922,
20918,
1920,
10383,
1930,
6559,
1927,
43,
3059,
13513,
2386,
1927,
8965,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8829663 | [
"Two",
"novel",
"(",
"1098insA",
" ",
"and",
"Y313H)",
"and",
"one",
"rare",
"(",
"R359Q",
"Y313H",
")",
"and",
"one",
"rare",
"(R359Q)",
"mutations",
"detected",
"in",
"exon",
"8",
"of",
"the",
"beta-glucocerebrosidase",
" ",
"gene",
"in",
"Gaucher's",
"disease",
"patients."
] | [
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
3,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0
] | Two novel ( 1098insA and Y313H) and one rare ( R359Q Y313H ) and one rare (R359Q) mutations detected in exon 8 of the beta-glucocerebrosidase gene in Gaucher's disease patients. | [
2,
2288,
4008,
12,
9359,
1025,
2925,
1019,
1930,
67,
6800,
1010,
1023,
13,
1930,
2340,
5844,
12,
19217,
7308,
1055,
67,
6800,
1010,
1023,
13,
1930,
2340,
5844,
12,
19217,
7308,
1055,
13,
3527,
3330,
1922,
7049,
28,
1927,
1920,
4666,
17,
3351,
29673,
18474,
12924,
3825,
4127,
2359,
1922,
4357,
21956,
11,
61,
2573,
2132,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
15514891 | [
"Polymorphisms",
"in",
"the",
"sclerosteosis/van",
"Buchem",
"disease",
" ",
"gene",
"(",
"SOST",
")",
"region",
"are",
"associated",
"with",
"bone-mineral",
"density",
"in",
"elderly",
"whites.",
"Osteoporosis",
"has",
"a",
"strong",
"genetic",
"component,",
"but",
"the",
"genes",
"involved",
"are",
"poorly",
"defined.",
"We",
"studied",
"whether",
"the",
"sclerosteosis/van",
"Buchem",
"disease",
" ",
"gene",
"(",
"SOST",
")",
"is",
"an",
"osteoporosis-risk",
"gene",
"by",
"examining",
"its",
"association",
"with",
"bone-mineral",
"density",
"(BMD).",
"Mutations",
"in",
"SOST",
" ",
"result",
"in",
"sclerosteosis,",
"and",
"alterations",
"in",
"the",
"SOST",
" ",
"gene",
"expression",
"may",
"be",
"causal",
"in",
"the",
"closely",
"related",
"van",
"Buchem",
"disease.",
"We",
"used",
"a",
"set",
"of",
"eight",
"polymorphisms",
"from",
"the",
"SOST",
" ",
"gene",
"region",
"to",
"genotype",
"1,939",
"elderly",
"men",
"and",
"women",
"from",
"a",
"large",
"population-based",
"prospective-cohort",
"study",
"of",
"Dutch",
"whites.",
"A",
"3-bp",
"insertion",
"(f=0.38)",
"in",
"the",
"presumed",
"SOST",
" ",
"promoter",
"region",
"(",
"SRP3",
")",
"was",
"associated",
"with",
"decreased",
"BMD",
"in",
"women",
"at",
"the",
"femoral",
"neck",
"(FN)",
"(P=.05)",
"and",
"lumbar",
"spine",
"(LS)",
"(P=.01),",
"with",
"evidence",
"of",
"an",
"allele-dose",
"effect",
"in",
"the",
"oldest",
"age",
"group",
"(P=.006).",
"Similarly,",
"a",
"G",
"variant",
"(f=0.40)",
"in",
"the",
"van",
"Buchem",
"deletion",
"region",
"(",
"SRP9",
")",
"was",
"associated",
"with",
"increased",
"BMD",
"in",
"men",
"at",
"the",
"FN",
"(P=.007)",
"and",
"LS",
"(P=.02).",
"In",
"both",
"cases,",
"differences",
"between",
"extreme",
"genotypes",
"reached",
"0.2",
"SD.",
"We",
"observed",
"no",
"genotype",
"effects",
"on",
"fracture",
"risk,",
"for",
"the",
"234",
"osteoporotic",
"fractures",
"validated",
"during",
"8.2",
"years",
"of",
"follow-up",
"and",
"for",
"the",
"146",
"vertebral",
"prevalent",
"fractures",
"analyzed.",
"We",
"did",
"not",
"find",
"association",
"between",
"any",
"of",
"several",
"frequent",
"haplotypes",
"across",
"the",
"SOST",
" ",
"gene",
"region",
"and",
"BMD.",
"We",
"did",
"find",
"evidence",
"of",
"additive",
"effects",
"of",
"SRP3",
" ",
"with",
"the",
"COLIA1",
" ",
"Sp1",
"polymorphism",
"but",
"not",
"with",
"haplotypes",
"of",
"3'",
"polymorphisms",
"in",
"the",
"vitamin-D",
"receptor",
"gene.",
"The",
"SOST-COLIA1",
"additive",
"effect",
"increased",
"with",
"age",
"and",
"reached",
"0.5",
"SD",
"difference",
"in",
"BMD",
"at",
"LS",
"in",
"the",
"oldest",
"age",
"group",
"(P=.02).",
"The",
"molecular",
"mechanism",
"whereby",
"these",
"moderate",
"SOST",
" ",
"genotype",
"effects",
"are",
"mediated",
"remains",
"to",
"be",
"elucidated,",
"but",
"it",
"is",
"likely",
"to",
"involve",
"differences",
"in",
"regulation",
"of",
"SOST",
"SOST-COLIA1",
" ",
"additive",
"effect",
"increased",
"with",
"age",
"and",
"reached",
"0.5",
"SD",
"difference",
"in",
"BMD",
"at",
"LS",
"in",
"the",
"oldest",
"age",
"group",
"(P=.02).",
"The",
"molecular",
"mechanism",
"whereby",
"these",
"moderate",
"SOST",
"genotype",
"effects",
"are",
"mediated",
"remains",
"to",
"be",
"elucidated,",
"but",
"it",
"is",
"likely",
"to",
"involve",
"differences",
"in",
"regulation",
"of",
"SOST",
"gene",
"expression."
] | [
0,
0,
0,
1,
2,
2,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Polymorphisms in the sclerosteosis/van Buchem disease gene ( SOST ) region are associated with bone-mineral density in elderly whites. Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene ( SOST ) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites. A 3-bp insertion (f=0.38) in the presumed SOST promoter region ( SRP3 ) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006). Similarly, a G variant (f=0.40) in the van Buchem deletion region ( SRP9 ) was associated with increased BMD in men at the FN (P=.007) and LS (P=.02). In both cases, differences between extreme genotypes reached 0.2 SD. We observed no genotype effects on fracture risk, for the 234 osteoporotic fractures validated during 8.2 years of follow-up and for the 146 vertebral prevalent fractures analyzed. We did not find association between any of several frequent haplotypes across the SOST gene region and BMD. We did find evidence of additive effects of SRP3 with the COLIA1 Sp1 polymorphism but not with haplotypes of 3' polymorphisms in the vitamin-D receptor gene. The SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST gene expression. | [
2,
8321,
1922,
1920,
8266,
18092,
2475,
19,
7409,
25485,
1987,
2573,
2359,
12,
17668,
1031,
13,
3031,
2032,
2458,
1956,
3622,
17,
8463,
3824,
1922,
7354,
15032,
18,
12340,
2258,
43,
3206,
3299,
4594,
16,
2308,
1920,
2628,
3286,
2032,
7865,
3608,
18,
2038,
3942,
3053,
1920,
8266,
18092,
2475,
19,
7409,
25485,
1987,
2573,
2359,
12,
17668,
1031,
13,
1977,
1925,
12340,
17,
2565,
2359,
2007,
8469,
2496,
3279,
1956,
3622,
17,
8463,
3824,
12,
9911,
13,
18,
3527,
1922,
17668,
1031,
3211,
1922,
8266,
18092,
2475,
16,
1930,
5996,
1922,
1920,
17668,
1031,
2359,
2294,
2278,
1998,
9263,
1922,
1920,
6538,
2712,
7409,
25485,
1987,
2573,
18,
2038,
2251,
43,
2735,
1927,
5066,
8321,
2037,
1920,
17668,
1031,
2359,
3031,
1942,
5619,
21,
16,
6156,
1026,
7354,
3925,
1930,
3089,
2037,
43,
3103,
2973,
17,
2454,
6315,
17,
4382,
2161,
1927,
15150,
15032,
18,
43,
23,
17,
4149,
7413,
12,
48,
33,
20,
18,
3738,
13,
1922,
1920,
15326,
17668,
1031,
4465,
3031,
12,
19939,
1010,
13,
1982,
2458,
1956,
3261,
9911,
1922,
3089,
2019,
1920,
9550,
7467,
12,
9945,
13,
12,
58,
33,
18,
2914,
13,
1930,
10781,
8859,
12,
6639,
13,
12,
58,
33,
18,
3287,
13,
16,
1956,
3095,
1927,
1925,
5465,
17,
3253,
2495,
1922,
1920,
22256,
2632,
2210,
12,
58,
33,
18,
12791,
13,
18,
4852,
16,
43,
49,
6031,
12,
48,
33,
20,
18,
3040,
13,
1922,
1920,
7409,
25485,
1987,
5541,
3031,
12,
19939,
1026,
13,
1982,
2458,
1956,
2502,
9911,
1922,
3925,
2019,
1920,
9945,
12,
58,
33,
18,
13298,
13,
1930,
6639,
12,
58,
33,
18,
5725,
13,
18,
1922,
2321,
2919,
16,
2886,
2192,
9848,
7059,
6690,
20,
18,
22,
4035,
18,
2038,
2528,
2239,
5619,
2564,
1990,
7515,
2565,
16,
1958,
1920,
19751,
25274,
9018,
6593,
2409,
28,
18,
22,
2739,
1927,
2396,
17,
2353,
1930,
1958,
1920,
13402,
13191,
8942,
9018,
3265,
18,
2038,
2811,
2084,
5387,
3279,
2192,
2967,
1927,
2980,
6439,
12149,
3436,
1920,
17668,
1031,
2359,
3031,
1930,
9911,
18,
2038,
2811,
5387,
3095,
1927,
10359,
2564,
1927,
19939,
1010,
1956,
1920,
5178,
4904,
15847,
8218,
2308,
2084,
1956,
12149,
1927,
23,
11,
8321,
1922,
1920,
6111,
17,
46,
3148,
2359,
18,
1920,
17668,
1031,
17,
5178,
4904,
10359,
2495,
2502,
1956,
2632,
1930,
6690,
20,
18,
25,
4035,
3175,
1922,
9911,
2019,
6639,
1922,
1920,
22256,
2632,
2210,
12,
58,
33,
18,
5725,
13,
18,
1920,
3272,
2856,
12507,
2144,
5086,
17668,
1031,
5619,
2564,
2032,
3434,
4497,
1942,
1998,
11900,
16,
2308,
2176,
1977,
3205,
1942,
8156,
2886,
1922,
3640,
1927,
17668,
1031,
17668,
1031,
17,
5178,
4904,
10359,
2495,
2502,
1956,
2632,
1930,
6690,
20,
18,
25,
4035,
3175,
1922,
9911,
2019,
6639,
1922,
1920,
22256,
2632,
2210,
12,
58,
33,
18,
5725,
13,
18,
1920,
3272,
2856,
12507,
2144,
5086,
17668,
1031,
5619,
2564,
2032,
3434,
4497,
1942,
1998,
11900,
16,
2308,
2176,
1977,
3205,
1942,
8156,
2886,
1922,
3640,
1927,
17668,
1031,
2359,
2294,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
21636067 | [
"X-linked",
"congenital",
"hypertrichosis",
"syndrome",
"is",
"associated",
"with",
"interchromosomal",
"insertions",
"mediated",
"by",
"a",
"human-specific",
"palindrome",
"near",
"SOX3",
".",
"X-linked",
"congenital",
"generalized",
"hypertrichosis",
"(CGH),",
"an",
"extremely",
"rare",
"condition",
"characterized",
"by",
"universal",
"overgrowth",
"of",
"terminal",
"hair,",
"was",
"first",
"mapped",
"to",
"chromosome",
"Xq24-q27.1",
"in",
"a",
"Mexican",
"family.",
"However,",
"the",
"underlying",
"genetic",
"defect",
"remains",
"unknown.",
"We",
"ascertained",
"a",
"large",
"Chinese",
"family",
"with",
"an",
"X-linked",
"congenital",
"hypertrichosis",
"syndrome",
"combining",
"CGH,",
"scoliosis,",
"and",
"spina",
"bifida",
"and",
"mapped",
"the",
"disease",
"locus",
"to",
"a",
"5.6",
"Mb",
"critical",
"region",
"within",
"the",
"interval",
"defined",
"by",
"the",
"previously",
"reported",
"Mexican",
"family.",
"Through",
"the",
"combination",
"of",
"a",
"high-resolution",
"copy-number",
"variation",
"(CNV)",
"scan",
"and",
"targeted",
"genomic",
"sequencing,",
"we",
"identified",
"an",
"interchromosomal",
"insertion",
"at",
"Xq27.1",
"of",
"a",
"125,577",
" ",
"bp",
"intragenic",
"fragment",
"of",
"COL23A1",
" ",
"on",
"5q35.3,",
"with",
"one",
"X",
"breakpoint",
"within",
"and",
"the",
"other",
"very",
"close",
"to",
"a",
"human-specific",
"short",
"palindromic",
"sequence",
"located",
"82",
"kb",
"downstream",
"of",
"SOX3",
".",
"In",
"the",
"Mexican",
"family,",
"we",
"found",
"an",
"interchromosomal",
"insertion",
"at",
"the",
"same",
"Xq27.1",
"site",
"of",
"a",
"300,036",
" ",
"bp",
"genomic",
"fragment",
"on",
"4q31.2,",
"encompassing",
"PRMT10",
" ",
"and",
"TMEM184C",
" ",
"and",
"involving",
"parts",
"of",
"ARHGAP10",
" ",
"and",
"EDNRA",
".",
"Notably,",
"both",
"of",
"the",
"two",
"X",
"breakpoints",
"were",
"within",
"the",
"short",
"palindrome.",
"The",
"two",
"palindrome-mediated",
"insertions",
"fully",
"segregate",
"with",
"the",
"CGH",
"phenotype",
"in",
"each",
"of",
"the",
"families,",
"and",
"the",
"CNV",
"gains",
"of",
"the",
"respective",
"autosomal",
"genomic",
"segments",
"are",
"not",
"present",
"in",
"the",
"public",
"database",
"and",
"were",
"not",
"found",
"in",
"1274",
"control",
"individuals.",
"Analysis",
"of",
"control",
"individuals",
"revealed",
"deletions",
"ranging",
"from",
"173",
" ",
"bp",
"to",
"9104",
" ",
"bp",
"at",
"the",
"site",
"of",
"the",
"insertions",
"with",
"no",
"phenotypic",
"consequence.",
"Taken",
"together,",
"our",
"results",
"strongly",
"support",
"the",
"pathogenicity",
"of",
"the",
"identified",
"insertions",
"and",
"establish",
"X-linked",
"congenital",
"hypertrichosis",
"syndrome",
"as",
"a",
"genomic",
"disorder."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | X-linked congenital hypertrichosis syndrome is associated with interchromosomal insertions mediated by a human-specific palindrome near SOX3 . X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome combining CGH, scoliosis, and spina bifida and mapped the disease locus to a 5.6 Mb critical region within the interval defined by the previously reported Mexican family. Through the combination of a high-resolution copy-number variation (CNV) scan and targeted genomic sequencing, we identified an interchromosomal insertion at Xq27.1 of a 125,577 bp intragenic fragment of COL23A1 on 5q35.3, with one X breakpoint within and the other very close to a human-specific short palindromic sequence located 82 kb downstream of SOX3 . In the Mexican family, we found an interchromosomal insertion at the same Xq27.1 site of a 300,036 bp genomic fragment on 4q31.2, encompassing PRMT10 and TMEM184C and involving parts of ARHGAP10 and EDNRA . Notably, both of the two X breakpoints were within the short palindrome. The two palindrome-mediated insertions fully segregate with the CGH phenotype in each of the families, and the CNV gains of the respective autosomal genomic segments are not present in the public database and were not found in 1274 control individuals. Analysis of control individuals revealed deletions ranging from 173 bp to 9104 bp at the site of the insertions with no phenotypic consequence. Taken together, our results strongly support the pathogenicity of the identified insertions and establish X-linked congenital hypertrichosis syndrome as a genomic disorder. | [
2,
66,
17,
4624,
9901,
4506,
4698,
2475,
4741,
1977,
2458,
1956,
8590,
6570,
13777,
2204,
9578,
15135,
3434,
2007,
43,
2616,
17,
2487,
29716,
4191,
4931,
9149,
1010,
18,
66,
17,
4624,
9901,
9612,
4506,
4698,
2475,
12,
26312,
13,
16,
1925,
8113,
5844,
2625,
4378,
2007,
10321,
27342,
1927,
4262,
7018,
16,
1982,
2561,
9225,
1942,
5597,
66,
23470,
1006,
17,
22808,
1027,
18,
21,
1922,
43,
17165,
3416,
18,
2406,
16,
1920,
5030,
3299,
7374,
4497,
5435,
18,
2038,
19231,
43,
3103,
7185,
3416,
1956,
1925,
66,
17,
4624,
9901,
4506,
4698,
2475,
4741,
9138,
26312,
16,
23534,
16,
1930,
7707,
1019,
21724,
1019,
1930,
9225,
1920,
2573,
6730,
1942,
43,
25,
18,
26,
5667,
4140,
3031,
2651,
1920,
4979,
3608,
2007,
1920,
3024,
2568,
17165,
3416,
18,
2596,
1920,
3921,
1927,
43,
2149,
17,
4885,
6983,
17,
2529,
4516,
12,
15590,
13,
4519,
1930,
5154,
4935,
4754,
16,
2038,
2899,
1925,
8590,
6570,
13777,
2204,
9578,
7413,
2019,
66,
23470,
1027,
18,
21,
1927,
43,
7151,
16,
4786,
1027,
4149,
27911,
7245,
5302,
1927,
2503,
4553,
4904,
1990,
25,
1055,
5798,
18,
23,
16,
1956,
2340,
66,
24698,
2651,
1930,
1920,
2303,
3345,
5428,
1942,
43,
2616,
17,
2487,
3662,
29716,
22771,
3244,
4810,
6175,
6633,
5863,
1927,
9149,
1010,
18,
1922,
1920,
17165,
3416,
16,
2038,
2435,
1925,
8590,
6570,
13777,
2204,
9578,
7413,
2019,
1920,
2841,
66,
23470,
1027,
18,
21,
3200,
1927,
43,
5255,
16,
23680,
4149,
4935,
5302,
1990,
24,
1055,
6800,
18,
22,
16,
17527,
27611,
2930,
1930,
22414,
21794,
1030,
1930,
5884,
7516,
1927,
25710,
19823,
2930,
1930,
3347,
16964,
1019,
18,
7388,
16,
2321,
1927,
1920,
2288,
66,
23800,
1985,
2651,
1920,
3662,
29716,
4191,
18,
1920,
2288,
29716,
4191,
17,
3434,
15135,
5437,
9762,
2010,
1956,
1920,
26312,
4629,
1922,
2362,
1927,
1920,
5767,
16,
1930,
1920,
15590,
13241,
1927,
1920,
7025,
13027,
4935,
7492,
2032,
2084,
2481,
1922,
1920,
4462,
5039,
1930,
1985,
2084,
2435,
1922,
10899,
1006,
2285,
3445,
18,
2333,
1927,
2285,
3445,
3404,
10550,
6485,
2037,
15853,
4149,
1942,
6550,
14743,
4149,
2019,
1920,
3200,
1927,
1920,
15135,
1956,
2239,
8189,
7749,
18,
4208,
4084,
16,
2342,
2274,
4937,
3373,
1920,
15903,
1927,
1920,
2899,
15135,
1930,
5389,
66,
17,
4624,
9901,
4506,
4698,
2475,
4741,
1966,
43,
4935,
4770,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
2,
0,
0,
0,
0,
1,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8651275 | [
"Guanidinoacetate",
"methyltransferase",
"deficiency:",
"the",
"first",
"inborn",
"error",
"of",
"creatine",
"metabolism",
"in",
"man.",
"In",
"two",
"children",
"with",
"an",
"accumulation",
"of",
"guanidinoacetate",
"in",
"brain",
"and",
"a",
"deficiency",
"of",
"creatine",
"in",
"blood,",
"a",
"severe",
"deficiency",
"of",
"guanidinoacetate",
"methyltransferase",
" ",
"(",
"GAMT",
")",
"activity",
"was",
"detected",
"in",
"the",
"liver.",
"Two",
"mutant",
"GAMT",
" ",
"alleles",
"were",
"identified",
"that",
"carried",
"a",
"single",
"base",
"substitution",
"within",
"a",
"5'",
"splice",
"site",
"or",
"a",
"13-nt",
"insertion",
"and",
"gave",
"rise",
"to",
"four",
"mutant",
"transcripts.",
"Three",
"of",
"the",
"transcripts",
"encode",
"truncated",
"polypeptides",
"that",
"lack",
"a",
"residue",
"known",
"to",
"be",
"critical",
"for",
"catalytic",
"activity",
"of",
"GAMT",
".",
"Deficiency",
"of",
"GAMT",
" ",
"is",
"the",
"first",
"inborn",
"error",
"of",
"creatine",
"metabolism.",
"It",
"causes",
"a",
"severe",
"developmental",
"delay",
"and",
"extrapyramidal",
"symptoms",
"in",
"early",
"infancy",
"and",
"is",
"treatable",
"by",
"oral",
"substitution",
"with",
"creatine."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase ( GAMT ) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT . Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine. | [
2,
13504,
22267,
18007,
16478,
6179,
30,
1920,
2561,
1922,
23419,
4622,
1927,
17784,
4714,
1922,
2323,
18,
1922,
2288,
3069,
1956,
1925,
4858,
1927,
13504,
22267,
18007,
1922,
3068,
1930,
43,
6179,
1927,
17784,
1922,
2877,
16,
43,
4010,
6179,
1927,
13504,
22267,
18007,
16478,
12,
9011,
1031,
13,
2455,
1982,
3330,
1922,
1920,
3568,
18,
2288,
3606,
9011,
1031,
7096,
1985,
2899,
1988,
4371,
43,
2957,
5170,
6636,
2651,
43,
25,
11,
10708,
3200,
2014,
43,
2590,
17,
5891,
7413,
1930,
7981,
7164,
1942,
3006,
3606,
6247,
18,
2559,
1927,
1920,
6247,
11107,
9530,
18633,
1988,
3630,
43,
6181,
3171,
1942,
1998,
4140,
1958,
6804,
2455,
1927,
9011,
1031,
18,
6179,
1927,
9011,
1031,
1977,
1920,
2561,
1922,
23419,
4622,
1927,
17784,
4714,
18,
2176,
5092,
43,
4010,
5878,
4989,
1930,
21346,
3553,
25238,
1923,
3601,
1922,
3120,
17591,
1930,
1977,
2297,
2115,
2007,
4726,
6636,
1956,
17784,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20652909 | [
"A",
"custom",
"148",
"gene-based",
"resequencing",
"chip",
"and",
"the",
"SNP",
"explorer",
"software:",
"new",
"tools",
"to",
"study",
"antibody",
"deficiency.",
"Hyper-IgM",
"syndrome",
"and",
"Common",
"Variable",
"Immunodeficiency",
"are",
"heterogeneous",
"disorders",
"characterized",
"by",
"a",
"predisposition",
"to",
"serious",
"infection",
"and",
"impaired",
"or",
"absent",
"neutralizing",
"antibody",
"responses.",
"Although",
"a",
"number",
"of",
"single",
"gene",
"defects",
"have",
"been",
"associated",
"with",
"these",
"immune",
"deficiency",
"disorders,",
"the",
"genetic",
"basis",
"of",
"many",
"cases",
"is",
"not",
"known.",
"To",
"facilitate",
"mutation",
"screening",
"in",
"patients",
"with",
"these",
"syndromes,",
"we",
"have",
"developed",
"a",
"custom",
"300-kb",
"resequencing",
"array,",
"the",
"Hyper-IgM/CVID",
"chip,",
"which",
"interrogates",
"1,576",
"coding",
"exons",
"and",
"intron-exon",
"junction",
"regions",
"from",
"148",
"genes",
"implicated",
"in",
"B-cell",
"development",
"and",
"immunoglobulin",
"isotype",
"switching.",
"Genomic",
"DNAs",
"extracted",
"from",
"patients",
"were",
"hybridized",
"to",
"the",
"array",
"using",
"a",
"high-throughput",
"protocol",
"for",
"target",
"sequence",
"amplification,",
"pooling,",
"and",
"hybridization.",
"A",
"Web-based",
"application,",
"SNP",
"Explorer,",
"was",
"developed",
"to",
"directly",
"analyze",
"and",
"visualize",
"the",
"single",
"nucleotide",
"polymorphism",
"(SNP)",
"annotation",
"and",
"for",
"quality",
"filtering.",
"Several",
"mutations",
"in",
"known",
"disease-susceptibility",
"genes",
"such",
"as",
"CD40LG",
",",
"TNFRSF13B",
",",
"IKBKG",
",",
"AICDA",
",",
"as",
"well",
"as",
"rare",
"nucleotide",
"changes",
"in",
"other",
"genes",
"such",
"as",
"TRAF3IP2",
",",
"were",
"identified",
"in",
"patient",
"DNA",
"samples",
"and",
"validated",
"by",
"direct",
"sequencing.",
"We",
"conclude",
"that",
"the",
"Hyper-IgM/CVID",
"chip",
"combined",
"with",
"SNP",
"Explorer",
"may",
"provide",
"a",
"cost-effective",
"tool",
"for",
"high-throughput",
"discovery",
"of",
"novel",
"mutations",
"among",
"hundreds",
"of",
"disease-relevant",
"genes",
"in",
"patients",
"with",
"inherited",
"antibody",
"deficiency."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A custom 148 gene-based resequencing chip and the SNP explorer software: new tools to study antibody deficiency. Hyper-IgM syndrome and Common Variable Immunodeficiency are heterogeneous disorders characterized by a predisposition to serious infection and impaired or absent neutralizing antibody responses. Although a number of single gene defects have been associated with these immune deficiency disorders, the genetic basis of many cases is not known. To facilitate mutation screening in patients with these syndromes, we have developed a custom 300-kb resequencing array, the Hyper-IgM/CVID chip, which interrogates 1,576 coding exons and intron-exon junction regions from 148 genes implicated in B-cell development and immunoglobulin isotype switching. Genomic DNAs extracted from patients were hybridized to the array using a high-throughput protocol for target sequence amplification, pooling, and hybridization. A Web-based application, SNP Explorer, was developed to directly analyze and visualize the single nucleotide polymorphism (SNP) annotation and for quality filtering. Several mutations in known disease-susceptibility genes such as CD40LG , TNFRSF13B , IKBKG , AICDA , as well as rare nucleotide changes in other genes such as TRAF3IP2 , were identified in patient DNA samples and validated by direct sequencing. We conclude that the Hyper-IgM/CVID chip combined with SNP Explorer may provide a cost-effective tool for high-throughput discovery of novel mutations among hundreds of disease-relevant genes in patients with inherited antibody deficiency. | [
2,
43,
10206,
13623,
2359,
17,
2454,
1995,
20626,
7333,
1930,
1920,
6821,
6414,
1005,
4187,
30,
2814,
6257,
1942,
2161,
3533,
6179,
18,
4194,
17,
10913,
4741,
1930,
3059,
4650,
13141,
2032,
8538,
4414,
4378,
2007,
43,
17757,
1942,
7433,
2909,
1930,
5761,
2014,
7685,
12130,
3533,
3387,
18,
2876,
43,
2529,
1927,
2957,
2359,
6007,
2162,
2252,
2458,
1956,
2144,
3743,
6179,
4414,
16,
1920,
3299,
4859,
1927,
3086,
2919,
1977,
2084,
3171,
18,
1942,
6628,
3979,
4449,
1922,
2132,
1956,
2144,
12688,
16,
2038,
2162,
3530,
43,
10206,
5255,
17,
6633,
1995,
20626,
6472,
16,
1920,
4194,
17,
10913,
19,
5519,
1960,
7333,
16,
2154,
20022,
2209,
21,
16,
4786,
1016,
5804,
10419,
1930,
10444,
17,
7049,
6910,
3451,
2037,
13623,
2628,
6835,
1922,
44,
17,
2024,
2740,
1930,
11837,
15436,
10880,
18,
4935,
20207,
5210,
2037,
2132,
1985,
17641,
1942,
1920,
6472,
2193,
43,
2149,
17,
9984,
4478,
1958,
2758,
3244,
6584,
16,
20893,
16,
1930,
8335,
18,
43,
8391,
17,
2454,
4722,
16,
6821,
6414,
1005,
16,
1982,
3530,
1942,
4103,
7125,
1930,
13159,
1920,
2957,
5489,
8218,
12,
6821,
13,
10452,
1930,
1958,
3455,
12433,
18,
2980,
3527,
1922,
3171,
2573,
17,
6461,
2628,
2427,
1966,
25918,
1029,
16,
4705,
5675,
5739,
11163,
16,
14502,
1014,
23254,
16,
14765,
3825,
16,
1966,
2486,
1966,
5844,
5489,
2840,
1922,
2303,
2628,
2427,
1966,
14803,
1010,
28787,
16,
1985,
2899,
1922,
2774,
2678,
2785,
1930,
6593,
2007,
3083,
4754,
18,
2038,
7676,
1988,
1920,
4194,
17,
10913,
19,
5519,
1960,
7333,
4252,
1956,
6821,
6414,
1005,
2278,
3394,
43,
4455,
17,
3655,
5229,
1958,
2149,
17,
9984,
7139,
1927,
4008,
3527,
2706,
15945,
1927,
2573,
17,
4494,
2628,
1922,
2132,
1956,
12911,
3533,
6179,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
2,
2,
0,
1,
2,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8488834 | [
"Insurance",
"commissioners",
"and",
"genetic",
"discrimination."
] | [
0,
0,
0,
0,
0
] | Insurance commissioners and genetic discrimination. | [
2,
9836,
14655,
2045,
1930,
3299,
8638,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
-100
] |
11180609 | [
"Three",
"novel",
"mutations",
"(",
"P760L",
",",
"L1305P",
",",
"Q1351Stop",
")",
"causing",
"Wilson",
"disease."
] | [
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
0,
0,
0
] | Three novel mutations ( P760L , L1305P , Q1351Stop ) causing Wilson disease. | [
2,
2559,
4008,
3527,
12,
19865,
5127,
1024,
16,
7554,
29058,
1034,
16,
22027,
5798,
26560,
27747,
13,
7538,
17711,
2573,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
-100
] |
12402345 | [
"Molecular",
"studies",
"in",
"mutase-deficient",
"(MUT)",
"methylmalonic",
"aciduria:",
"identification",
"of",
"five",
"novel",
"mutations.",
"Mutase-deficient",
"(MUT)",
"methylmalonic",
"aciduria",
"(MMA)",
"is",
"an",
"autosomal",
"recessive",
"inborn",
"error",
"of",
"organic",
"acid",
"metabolism,",
"resulting",
"from",
"a",
"functional",
"defect",
"in",
"the",
"nuclear",
"encoded",
"mitochondrial",
"enzyme",
"methylmalonyl-CoA",
"mutase",
"(MCM)",
"(EC.5.4.99.2).",
"The",
"enzyme",
"requires",
"5'-deoxyadenosylcobalamin",
"as",
"a",
"cofactor.",
"Isolated",
"MMA",
"results",
"from",
"either",
"apoenzyme",
"or",
"cofactor",
"defects,",
"and",
"is",
"classified",
"into",
"several",
"genotypic",
"classes",
"and",
"complementation",
"groups.",
"These",
"are",
"designated",
"mut(-)",
"or",
"mut(0)",
"(together",
"termed",
"mut),",
"depending",
"on",
"minimal",
"or",
"no",
"apoenzyme",
"activity",
"respectively",
"and",
"cobalamin",
"A",
"or",
"B",
"(cbl",
"A/B)",
"for",
"cofactor",
"defects.",
"To",
"date",
"various",
"studies",
"have",
"identified",
"over",
"53",
"disease-causing",
"mutations",
"from",
"patients",
"with",
"mut(0/-)",
"MMA.",
"These",
"are",
"predominantly",
"missense/nonsense",
"nucleotide",
"substitutions.",
"In",
"this",
"study,",
"we",
"report",
"the",
"genotype",
"analysis",
"on",
"7",
"patients",
"diagnosed",
"with",
"mut",
"MMA.",
"Five",
"novel",
"mutations",
"were",
"identified",
"(",
"R403stop",
",",
"497delG",
",",
"P615T",
",",
"208delG",
" ",
"and",
"R467stop",
")",
"and",
"one",
"novel",
"polymorphism",
"(",
"c712A->G",
").",
"The",
"previously",
"reported",
"R228Q",
" ",
"mutation",
"was",
"found",
"in",
"one",
"patient,",
"who",
"is",
"a",
"compound",
"heterozygote",
"for",
"this",
"mutation",
"and",
"the",
"R467stop",
"mutation.",
"A",
"recently",
"reported",
"N219Y",
"R467stop",
" ",
"mutation.",
"A",
"recently",
"reported",
"N219Y",
"mutation",
"was",
"found",
"in",
"one",
"patient.",
"The",
"497delG",
" ",
"mutation",
"was",
"detected",
"as",
"a",
"homozygous",
"deletion.",
"The",
"remaining",
"mutations",
"were",
"observed",
"in",
"compound",
"heterozygotes,",
"with",
"the",
"second",
"mutation",
"yet",
"to",
"be",
"identified.",
"Many",
"of",
"the",
"unidentified",
"mutations",
"may",
"occur",
"within",
"the",
"promotor",
"or",
"intronic",
"regions."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Molecular studies in mutase-deficient (MUT) methylmalonic aciduria: identification of five novel mutations. Mutase-deficient (MUT) methylmalonic aciduria (MMA) is an autosomal recessive inborn error of organic acid metabolism, resulting from a functional defect in the nuclear encoded mitochondrial enzyme methylmalonyl-CoA mutase (MCM) (EC.5.4.99.2). The enzyme requires 5'-deoxyadenosylcobalamin as a cofactor. Isolated MMA results from either apoenzyme or cofactor defects, and is classified into several genotypic classes and complementation groups. These are designated mut(-) or mut(0) (together termed mut), depending on minimal or no apoenzyme activity respectively and cobalamin A or B (cbl A/B) for cofactor defects. To date various studies have identified over 53 disease-causing mutations from patients with mut(0/-) MMA. These are predominantly missense/nonsense nucleotide substitutions. In this study, we report the genotype analysis on 7 patients diagnosed with mut MMA. Five novel mutations were identified ( R403stop , 497delG , P615T , 208delG and R467stop ) and one novel polymorphism ( c712A->G ). The previously reported R228Q mutation was found in one patient, who is a compound heterozygote for this mutation and the R467stop mutation. A recently reported N219Y R467stop mutation. A recently reported N219Y mutation was found in one patient. The 497delG mutation was detected as a homozygous deletion. The remaining mutations were observed in compound heterozygotes, with the second mutation yet to be identified. Many of the unidentified mutations may occur within the promotor or intronic regions. | [
2,
3272,
2351,
1922,
2446,
2051,
17,
5778,
12,
2446,
13,
4963,
9578,
3490,
2687,
8754,
30,
4824,
1927,
3628,
4008,
3527,
18,
2446,
2051,
17,
5778,
12,
2446,
13,
4963,
9578,
3490,
2687,
8754,
12,
29025,
13,
1977,
1925,
13027,
13992,
1922,
23419,
4622,
1927,
6805,
2687,
4714,
16,
3864,
2037,
43,
3183,
7374,
1922,
1920,
4254,
7905,
4596,
4113,
4963,
9578,
12831,
17,
10027,
2446,
2051,
12,
15379,
13,
12,
3270,
18,
25,
18,
24,
18,
4922,
18,
22,
13,
18,
1920,
4113,
5474,
25,
11,
17,
16333,
10185,
11731,
4879,
5949,
3717,
1966,
43,
15155,
18,
3937,
29025,
2274,
2037,
3108,
10290,
1022,
9318,
2014,
15155,
6007,
16,
1930,
1977,
5947,
2460,
2980,
19251,
7190,
1930,
17465,
2671,
18,
2144,
2032,
10176,
2446,
12,
17,
13,
2014,
2446,
12,
20,
13,
12,
4084,
10266,
2446,
13,
16,
6362,
1990,
6343,
2014,
2239,
10290,
1022,
9318,
2455,
2763,
1930,
18477,
3717,
43,
2014,
44,
12,
17703,
43,
19,
44,
13,
1958,
15155,
6007,
18,
1942,
5699,
3425,
2351,
2162,
2899,
2338,
4522,
2573,
17,
7538,
3527,
2037,
2132,
1956,
2446,
12,
20,
19,
17,
13,
29025,
18,
2144,
2032,
7700,
13519,
19,
19605,
5489,
10682,
18,
1922,
2052,
2161,
16,
2038,
3809,
1920,
5619,
2333,
1990,
27,
2132,
5377,
1956,
2446,
29025,
18,
3628,
4008,
3527,
1985,
2899,
12,
23103,
12962,
2156,
2011,
16,
29336,
16878,
1029,
16,
21139,
3962,
1031,
16,
17025,
16878,
1029,
1930,
23103,
6038,
2156,
2011,
13,
1930,
2340,
4008,
8218,
12,
19677,
3112,
1019,
17,
34,
49,
13,
18,
1920,
3024,
2568,
7261,
4839,
1055,
3979,
1982,
2435,
1922,
2340,
2774,
16,
2746,
1977,
43,
3547,
28070,
1958,
2052,
3979,
1930,
1920,
23103,
6038,
2156,
2011,
3979,
18,
43,
3998,
2568,
9585,
4136,
1012,
23103,
6038,
2156,
2011,
3979,
18,
43,
3998,
2568,
9585,
4136,
1012,
3979,
1982,
2435,
1922,
2340,
2774,
18,
1920,
29336,
16878,
1029,
3979,
1982,
3330,
1966,
43,
9419,
5541,
18,
1920,
5719,
3527,
1985,
2528,
1922,
3547,
22910,
16,
1956,
1920,
2812,
3979,
4898,
1942,
1998,
2899,
18,
3086,
1927,
1920,
18788,
3527,
2278,
4704,
2651,
1920,
4212,
1924,
2014,
20341,
3451,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8019568 | [
"Phenylketonuria",
"in",
"China:",
"identification",
"and",
"characterization",
"of",
"three",
"novel",
"nucleotide",
"substitutions",
"in",
"the",
"human",
"phenylalanine",
"hydroxylase",
" ",
"gene."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0
] | Phenylketonuria in China: identification and characterization of three novel nucleotide substitutions in the human phenylalanine hydroxylase gene. | [
2,
7971,
18540,
1916,
8754,
1922,
5429,
30,
4824,
1930,
7285,
1927,
2559,
4008,
5489,
10682,
1922,
1920,
2616,
17388,
16324,
2359,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
-100
] |
11112662 | [
"A",
"narrow",
"segment",
"of",
"maternal",
"uniparental",
"disomy",
"of",
"chromosome",
"7q31-qter",
"in",
"Silver-Russell",
"syndrome",
"delimits",
"a",
"candidate",
"gene",
"region.",
"Maternal",
"uniparental",
"disomy",
"of",
"chromosome",
"7",
"(matUPD7),",
"the",
"inheritance",
"of",
"both",
"chromosomes",
"from",
"only",
"the",
"mother,",
"is",
"observed",
"in",
"approximately",
"10%",
"of",
"patients",
"with",
"Silver-Russell",
"syndrome",
"(SRS).",
"It",
"has",
"been",
"suggested",
"that",
"at",
"least",
"one",
"imprinted",
"gene",
"that",
"regulates",
"growth",
"and",
"development",
"resides",
"on",
"human",
"chromosome",
"7.",
"To",
"date,",
"three",
"imprinted",
"genes-",
"PEG1",
"/MEST,",
"gamma2-COP,",
" ",
"and",
"GRB10",
"-have",
"been",
"identified",
"on",
"chromosome",
"7,",
"but",
"their",
"role",
"in",
"the",
"etiology",
"of",
"SRS",
"remains",
"uncertain.",
"In",
"a",
"systematic",
"screening",
"with",
"microsatellite",
"markers,",
"for",
"matUPD7",
"cases",
"among",
"patients",
"with",
"SRS,",
"we",
"identified",
"a",
"patient",
"who",
"had",
"a",
"small",
"segment",
"of",
"matUPD7",
"and",
"biparental",
"inheritance",
"of",
"the",
"remainder",
"of",
"chromosome",
"7.",
"Such",
"a",
"pattern",
"may",
"be",
"explained",
"by",
"somatic",
"recombination",
"in",
"the",
"zygote.",
"The",
"matUPD7",
"segment",
"at",
"7q31-qter",
"extends",
"for",
"35",
"Mb",
"and",
"includes",
"the",
"imprinted",
"gene",
"cluster",
"of",
"PEG1",
"/MEST",
"and",
"gamma2-COP",
" ",
"at",
"7q32.",
"GRB10",
"MEST",
",",
"gamma2-COP,",
"and",
"GRB10-have",
"been",
"identified",
"on",
"chromosome",
"7,",
"but",
"their",
"role",
"in",
"the",
"etiology",
"of",
"SRS",
"remains",
"uncertain.",
"In",
"a",
"systematic",
"screening",
"with",
"microsatellite",
"markers,",
"for",
"matUPD7",
"cases",
"among",
"patients",
"with",
"SRS,",
"we",
"identified",
"a",
"patient",
"who",
"had",
"a",
"small",
"segment",
"of",
"matUPD7",
"and",
"biparental",
"inheritance",
"of",
"the",
"remainder",
"of",
"chromosome",
"7.",
"Such",
"a",
"pattern",
"may",
"be",
"explained",
"by",
"somatic",
"recombination",
"in",
"the",
"zygote.",
"The",
"matUPD7",
"segment",
"at",
"7q31-qter",
"extends",
"for",
"35",
"Mb",
"and",
"includes",
"the",
"imprinted",
"gene",
"cluster",
"of",
"PEG1/",
"MEST",
" ",
"and",
"gamma2-COP",
"at",
"7q32.",
"GRB10",
"at",
"7p11.2-p12",
"is",
"located",
"within",
"a",
"region",
"of",
"biparental",
"inheritance.",
"Although",
"partial",
"UPD",
"has",
"previously",
"been",
"reported",
"for",
"chromosomes",
"6,",
"11,",
"14,",
"and",
"15,",
"this",
"is",
"the",
"first",
"report",
"of",
"a",
"patient",
"with",
"SRS",
"who",
"has",
"segmental",
"matUPD7.",
"Our",
"findings",
"delimit",
"a",
"candidate",
"imprinted",
"region",
"sufficient",
"to",
"cause",
"SRS."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region. Maternal uniparental disomy of chromosome 7 (matUPD7), the inheritance of both chromosomes from only the mother, is observed in approximately 10% of patients with Silver-Russell syndrome (SRS). It has been suggested that at least one imprinted gene that regulates growth and development resides on human chromosome 7. To date, three imprinted genes- PEG1 /MEST, gamma2-COP, and GRB10 -have been identified on chromosome 7, but their role in the etiology of SRS remains uncertain. In a systematic screening with microsatellite markers, for matUPD7 cases among patients with SRS, we identified a patient who had a small segment of matUPD7 and biparental inheritance of the remainder of chromosome 7. Such a pattern may be explained by somatic recombination in the zygote. The matUPD7 segment at 7q31-qter extends for 35 Mb and includes the imprinted gene cluster of PEG1 /MEST and gamma2-COP at 7q32. GRB10 MEST , gamma2-COP, and GRB10-have been identified on chromosome 7, but their role in the etiology of SRS remains uncertain. In a systematic screening with microsatellite markers, for matUPD7 cases among patients with SRS, we identified a patient who had a small segment of matUPD7 and biparental inheritance of the remainder of chromosome 7. Such a pattern may be explained by somatic recombination in the zygote. The matUPD7 segment at 7q31-qter extends for 35 Mb and includes the imprinted gene cluster of PEG1/ MEST and gamma2-COP at 7q32. GRB10 at 7p11.2-p12 is located within a region of biparental inheritance. Although partial UPD has previously been reported for chromosomes 6, 11, 14, and 15, this is the first report of a patient with SRS who has segmental matUPD7. Our findings delimit a candidate imprinted region sufficient to cause SRS. | [
2,
43,
8400,
5367,
1927,
5509,
15943,
2768,
4905,
1923,
2054,
3542,
1927,
5597,
27,
1055,
6800,
17,
8877,
1915,
1922,
11078,
17,
28975,
4741,
2723,
1980,
2664,
43,
6610,
2359,
3031,
18,
5509,
15943,
2768,
4905,
1923,
2054,
3542,
1927,
5597,
27,
12,
2888,
3481,
29678,
13,
16,
1920,
15762,
1927,
2321,
8597,
2037,
2444,
1920,
7999,
16,
1977,
2528,
1922,
3993,
2119,
9,
1927,
2132,
1956,
11078,
17,
28975,
4741,
12,
16018,
13,
18,
2176,
2258,
2252,
3978,
1988,
2019,
3464,
2340,
22463,
2359,
1988,
7014,
2905,
1930,
2740,
21850,
1990,
2616,
5597,
27,
18,
1942,
5699,
16,
2559,
22463,
2628,
17,
7404,
1009,
19,
4438,
1031,
16,
7034,
1028,
17,
3725,
16,
1930,
2398,
5090,
1008,
17,
2162,
2252,
2899,
1990,
5597,
27,
16,
2308,
2310,
2770,
1922,
1920,
10383,
1927,
16018,
4497,
7323,
18,
1922,
43,
5614,
4449,
1956,
16069,
4432,
16,
1958,
2888,
3481,
29678,
2919,
2706,
2132,
1956,
16018,
16,
2038,
2899,
43,
2774,
2746,
2430,
43,
2858,
5367,
1927,
2888,
3481,
29678,
1930,
8446,
2768,
4905,
1923,
15762,
1927,
1920,
15834,
1927,
5597,
27,
18,
2427,
43,
3114,
2278,
1998,
6094,
2007,
8548,
7827,
1922,
1920,
16160,
7229,
18,
1920,
2888,
3481,
29678,
5367,
2019,
27,
1055,
6800,
17,
8877,
1915,
13957,
1958,
3259,
5667,
1930,
5921,
1920,
22463,
2359,
4377,
1927,
7404,
1009,
19,
4438,
1031,
1930,
7034,
1028,
17,
3725,
2019,
27,
1055,
6763,
18,
2398,
5090,
1008,
4438,
1031,
16,
7034,
1028,
17,
3725,
16,
1930,
2398,
5090,
1008,
17,
2162,
2252,
2899,
1990,
5597,
27,
16,
2308,
2310,
2770,
1922,
1920,
10383,
1927,
16018,
4497,
7323,
18,
1922,
43,
5614,
4449,
1956,
16069,
4432,
16,
1958,
2888,
3481,
29678,
2919,
2706,
2132,
1956,
16018,
16,
2038,
2899,
43,
2774,
2746,
2430,
43,
2858,
5367,
1927,
2888,
3481,
29678,
1930,
8446,
2768,
4905,
1923,
15762,
1927,
1920,
15834,
1927,
5597,
27,
18,
2427,
43,
3114,
2278,
1998,
6094,
2007,
8548,
7827,
1922,
1920,
16160,
7229,
18,
1920,
2888,
3481,
29678,
5367,
2019,
27,
1055,
6800,
17,
8877,
1915,
13957,
1958,
3259,
5667,
1930,
5921,
1920,
22463,
2359,
4377,
1927,
7404,
1009,
19,
4438,
1031,
1930,
7034,
1028,
17,
3725,
2019,
27,
1055,
6763,
18,
2398,
5090,
1008,
2019,
27,
5113,
1009,
18,
22,
17,
28443,
1977,
4810,
2651,
43,
3031,
1927,
8446,
2768,
4905,
1923,
15762,
18,
2876,
5740,
8831,
2258,
3024,
2252,
2568,
1958,
8597,
26,
16,
2513,
16,
2607,
16,
1930,
2461,
16,
2052,
1977,
1920,
2561,
3809,
1927,
43,
2774,
1956,
16018,
2746,
2258,
16294,
2888,
3481,
29678,
18,
2342,
3056,
2723,
1980,
1932,
43,
6610,
22463,
3031,
5409,
1942,
3936,
16018,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
1,
2,
2,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
11519010 | [
"Evidence",
"of",
"linkage",
"with",
"HLA-DR",
" ",
"in",
"DRB1*15-negative",
"families",
"with",
"multiple",
"sclerosis.",
"The",
"importance",
"of",
"the",
"HLA-DR",
" ",
"locus",
"to",
"multiple",
"sclerosis",
"(MS)",
"susceptibility",
"was",
"assessed",
"in",
"542",
"sib",
"pairs",
"with",
"MS",
"and",
"in",
"their",
"families.",
"By",
"genotyping",
"1,978",
"individuals",
"for",
"HLA-DRB1",
" ",
"alleles,",
"we",
"confirmed",
"the",
"well-established",
"association",
"of",
"MS",
"with",
"HLA-DRB1",
"*15",
"(",
"HLA-DRB1",
"*1501",
"and",
"HLA-DRB5",
"*0101),",
"by",
"the",
"transmission/disequilibrium",
"test",
"(chi2=138.3;",
"P<.0001).",
"We",
"obtained",
"significant",
"evidence",
"of",
"linkage",
"throughout",
"the",
"whole",
"data",
"set",
"(mlod=4.09;",
"59.9%",
"sharing).",
"Surprisingly,",
"similar",
"sharing",
"was",
"also",
"observed",
"in",
"58",
"families",
"in",
"which",
"both",
"parents",
"lacked",
"the",
"DRB1",
"*15",
"allele",
"(mlod=1.56;",
"62.7%",
"sharing;",
"P=.0081).",
"Our",
"findings",
"suggest",
"that",
"the",
"notion",
"that",
"HLA-DRB1",
"*15",
"is",
"the",
"sole",
"major-histocompatibility-complex",
"determinant",
"of",
"susceptibility",
"in",
"northern-European",
"populations",
"with",
"MS",
"may",
"be",
"incorrect.",
"It",
"remains",
"possible",
"that",
"the",
"association",
"of",
"MS",
"with",
"HLA-DRB1",
"*15",
"is",
"due",
"to",
"linkage",
"disequilibrium",
"with",
"a",
"nearby",
"locus",
"and/or",
"to",
"the",
"presence",
"of",
"disease-influencing",
"allele(s)",
"in",
"DRB1",
"*15-negative",
"haplotypes."
] | [
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0
] | Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis. The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1 *15 ( HLA-DRB1 *1501 and HLA-DRB5 *0101), by the transmission/disequilibrium test (chi2=138.3; P<.0001). We obtained significant evidence of linkage throughout the whole data set (mlod=4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1 *15 allele (mlod=1.56; 62.7% sharing; P=.0081). Our findings suggest that the notion that HLA-DRB1 *15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1 *15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1 *15-negative haplotypes. | [
2,
3095,
1927,
8611,
1956,
7225,
17,
2324,
1922,
22202,
14,
2461,
17,
3136,
5767,
1956,
3137,
11484,
18,
1920,
4737,
1927,
1920,
7225,
17,
2324,
6730,
1942,
3137,
11484,
12,
3012,
13,
6461,
1982,
3683,
1922,
4584,
1028,
9643,
5803,
1956,
3012,
1930,
1922,
2310,
5767,
18,
2007,
10667,
21,
16,
5749,
1025,
3445,
1958,
7225,
17,
22202,
7096,
16,
2038,
3982,
1920,
2486,
17,
4379,
3279,
1927,
3012,
1956,
7225,
17,
22202,
14,
2461,
12,
7225,
17,
22202,
14,
5493,
1009,
1930,
7225,
17,
2324,
24462,
14,
17314,
1009,
13,
16,
2007,
1920,
5303,
19,
19264,
2648,
12,
7368,
1028,
33,
12830,
18,
23,
31,
58,
32,
18,
6060,
13,
18,
2038,
2926,
2228,
3095,
1927,
8611,
5264,
1920,
4292,
2230,
2735,
12,
2646,
1986,
33,
24,
18,
7102,
31,
4777,
18,
29,
9,
10763,
13,
18,
10091,
16,
2551,
10763,
1982,
2222,
2528,
1922,
4804,
5767,
1922,
2154,
2321,
5853,
15115,
1920,
22202,
14,
2461,
5465,
12,
2646,
1986,
33,
21,
18,
4489,
31,
5374,
18,
27,
9,
10763,
31,
58,
33,
18,
13587,
1009,
13,
18,
2342,
3056,
3220,
1988,
1920,
10316,
1988,
7225,
17,
22202,
14,
2461,
1977,
1920,
12168,
3044,
17,
22836,
17,
2796,
12483,
1927,
6461,
1922,
9250,
17,
6785,
4098,
1956,
3012,
2278,
1998,
12984,
18,
2176,
4497,
3216,
1988,
1920,
3279,
1927,
3012,
1956,
7225,
17,
22202,
14,
2461,
1977,
2810,
1942,
8611,
19264,
1956,
43,
15485,
6730,
1930,
19,
2014,
1942,
1920,
2990,
1927,
2573,
17,
11623,
5465,
12,
61,
13,
1922,
22202,
14,
2461,
17,
3136,
12149,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
-100
] |
9683604 | [
"From",
"amplification",
"to",
"gene",
"in",
"thyroid",
"cancer:",
"a",
"high-resolution",
"mapped",
"bacterial-artificial-chromosome",
"resource",
"for",
"cancer",
"chromosome",
"aberrations",
"guides",
"gene",
"discovery",
"after",
"comparative",
"genome",
"hybridization.",
"Chromosome",
"rearrangements",
"associated",
"with",
"neoplasms",
"provide",
"a",
"rich",
"resource",
"for",
"definition",
"of",
"the",
"pathways",
"of",
"tumorigenesis.",
"The",
"power",
"of",
"comparative",
"genome",
"hybridization",
"(CGH)",
"to",
"identify",
"novel",
"genes",
"depends",
"on",
"the",
"existence",
"of",
"suitable",
"markers,",
"which",
"are",
"lacking",
"throughout",
"most",
"of",
"the",
"genome.",
"We",
"now",
"report",
"a",
"general",
"approach",
"that",
"translates",
"CGH",
"data",
"into",
"higher-resolution",
"genomic-clone",
"data",
"that",
"are",
"then",
"used",
"to",
"define",
"the",
"genes",
"located",
"in",
"aneuploid",
"regions.",
"We",
"used",
"CGH",
"to",
"study",
"33",
"thyroid-tumor",
"DNAs",
"and",
"two",
"tumor-cell-line",
"DNAs.",
"The",
"results",
"revealed",
"amplifications",
"of",
"chromosome",
"band",
"2p21,",
"with",
"less-intense",
"amplification",
"on",
"2p13,",
"19q13.1,",
"and",
"1p36",
"and",
"with",
"least-intense",
"amplification",
"on",
"1p34,",
"1q42,",
"5q31,",
"5q33-34,",
"9q32-34,",
"and",
"14q32.",
"To",
"define",
"the",
"2p21",
"region",
"amplified,",
"a",
"dense",
"array",
"of",
"373",
"FISH-mapped",
"chromosome",
"2",
"bacterial",
"artificial",
"chromosomes",
"(BACs)",
"was",
"constructed,",
"and",
"87",
"of",
"these",
"were",
"hybridized",
"to",
"a",
"tumor-cell",
"line.",
"Four",
"BACs",
"carried",
"genomic",
"DNA",
"that",
"was",
"amplified",
"in",
"these",
"cells.",
"The",
"maximum",
"amplified",
"region",
"was",
"narrowed",
"to",
"3-6",
"Mb",
"by",
"multicolor",
"FISH",
"with",
"the",
"flanking",
"BACs,",
"and",
"the",
"minimum",
"amplicon",
"size",
"was",
"defined",
"by",
"a",
"contig",
"of",
"420",
"kb.",
"Sequence",
"analysis",
"of",
"the",
"amplified",
"BAC",
"1D9",
"revealed",
"a",
"fragment",
"of",
"the",
"gene,",
"encoding",
"protein",
"kinase",
"C",
"epsilon",
" ",
"(PKCepsilon),",
" ",
"that",
"was",
"then",
"shown",
"to",
"be",
"amplified",
"and",
"rearranged",
"in",
"tumor",
"cells.",
"In",
"summary,",
"CGH",
"combined",
"with",
"a",
"dense",
"mapped",
"resource",
"of",
"BACs",
"and",
"large-scale",
"sequencing",
"has",
"led",
"directly",
"to",
"the",
"definition",
"of",
"PKCepsilon",
" ",
"as",
"a",
"previously",
"unmapped",
"candidate",
"gene",
"involved",
"in",
"thyroid",
"tumorigenesis."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | From amplification to gene in thyroid cancer: a high-resolution mapped bacterial-artificial-chromosome resource for cancer chromosome aberrations guides gene discovery after comparative genome hybridization. Chromosome rearrangements associated with neoplasms provide a rich resource for definition of the pathways of tumorigenesis. The power of comparative genome hybridization (CGH) to identify novel genes depends on the existence of suitable markers, which are lacking throughout most of the genome. We now report a general approach that translates CGH data into higher-resolution genomic-clone data that are then used to define the genes located in aneuploid regions. We used CGH to study 33 thyroid-tumor DNAs and two tumor-cell-line DNAs. The results revealed amplifications of chromosome band 2p21, with less-intense amplification on 2p13, 19q13.1, and 1p36 and with least-intense amplification on 1p34, 1q42, 5q31, 5q33-34, 9q32-34, and 14q32. To define the 2p21 region amplified, a dense array of 373 FISH-mapped chromosome 2 bacterial artificial chromosomes (BACs) was constructed, and 87 of these were hybridized to a tumor-cell line. Four BACs carried genomic DNA that was amplified in these cells. The maximum amplified region was narrowed to 3-6 Mb by multicolor FISH with the flanking BACs, and the minimum amplicon size was defined by a contig of 420 kb. Sequence analysis of the amplified BAC 1D9 revealed a fragment of the gene, encoding protein kinase C epsilon (PKCepsilon), that was then shown to be amplified and rearranged in tumor cells. In summary, CGH combined with a dense mapped resource of BACs and large-scale sequencing has led directly to the definition of PKCepsilon as a previously unmapped candidate gene involved in thyroid tumorigenesis. | [
2,
2037,
6584,
1942,
2359,
1922,
6918,
2539,
30,
43,
2149,
17,
4885,
9225,
4543,
17,
9467,
17,
5597,
7965,
1958,
2539,
5597,
16303,
24420,
2359,
7139,
2256,
8255,
3843,
8335,
18,
5597,
13955,
2458,
1956,
15347,
3394,
43,
5536,
7965,
1958,
6600,
1927,
1920,
3873,
1927,
11472,
18,
1920,
4215,
1927,
8255,
3843,
8335,
12,
26312,
13,
1942,
3512,
4008,
2628,
7315,
1990,
1920,
8627,
1927,
6947,
4432,
16,
2154,
2032,
7046,
5264,
2501,
1927,
1920,
3843,
18,
2038,
5195,
3809,
43,
3335,
2998,
1988,
27405,
26312,
2230,
2460,
2580,
17,
4885,
4935,
17,
7842,
2230,
1988,
2032,
2759,
2251,
1942,
7425,
1920,
2628,
4810,
1922,
19257,
3451,
18,
2038,
2251,
26312,
1942,
2161,
3401,
6918,
17,
2798,
20207,
1930,
2288,
2798,
17,
2024,
17,
2823,
20207,
18,
1920,
2274,
3404,
24272,
1927,
5597,
5472,
21981,
4716,
16,
1956,
2941,
17,
10702,
6584,
1990,
21981,
3633,
16,
2282,
16886,
1010,
18,
21,
16,
1930,
21727,
5677,
1930,
1956,
3464,
17,
10702,
6584,
1990,
21727,
4857,
16,
28798,
6852,
16,
25,
1055,
6800,
16,
25,
1055,
6498,
17,
3540,
16,
29,
1055,
6763,
17,
3540,
16,
1930,
2607,
1055,
6763,
18,
1942,
7425,
1920,
21981,
4716,
3031,
7006,
16,
43,
10472,
6472,
1927,
25584,
5724,
17,
9225,
5597,
22,
4543,
9467,
8597,
12,
8175,
1036,
13,
1982,
6857,
16,
1930,
5783,
1927,
2144,
1985,
17641,
1942,
43,
2798,
17,
2024,
2823,
18,
3006,
8175,
1036,
4371,
4935,
2678,
1988,
1982,
7006,
1922,
2144,
2094,
18,
1920,
4419,
7006,
3031,
1982,
8400,
1919,
1942,
23,
17,
26,
5667,
2007,
8844,
18778,
5724,
1956,
1920,
12679,
8175,
1036,
16,
1930,
1920,
6081,
17686,
3081,
1982,
3608,
2007,
43,
10988,
1927,
19350,
6633,
18,
3244,
2333,
1927,
1920,
7006,
8175,
8046,
1026,
3404,
43,
5302,
1927,
1920,
2359,
16,
5797,
2213,
4016,
45,
22206,
12,
8425,
9431,
16920,
13,
16,
1988,
1982,
2759,
2522,
1942,
1998,
7006,
1930,
26669,
1922,
2798,
2094,
18,
1922,
6099,
16,
26312,
4252,
1956,
43,
10472,
9225,
7965,
1927,
8175,
1036,
1930,
3103,
17,
3536,
4754,
2258,
4866,
4103,
1942,
1920,
6600,
1927,
8425,
9431,
16920,
1966,
43,
3024,
11255,
6688,
6610,
2359,
3286,
1922,
6918,
11472,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
1,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
15988677 | [
"A",
"combined",
"genomewide",
"linkage",
"scan",
"of",
"1,233",
"families",
"for",
"prostate",
"cancer-susceptibility",
"genes",
"conducted",
"by",
"the",
"international",
"consortium",
"for",
"prostate",
"cancer",
"genetics.",
"Evidence",
"of",
"the",
"existence",
"of",
"major",
"prostate",
"cancer",
"(PC)-susceptibility",
"genes",
"has",
"been",
"provided",
"by",
"multiple",
"segregation",
"analyses.",
"Although",
"genomewide",
"screens",
"have",
"been",
"performed",
"in",
"over",
"a",
"dozen",
"independent",
"studies,",
"few",
"chromosomal",
"regions",
"have",
"been",
"consistently",
"identified",
"as",
"regions",
"of",
"interest.",
"One",
"of",
"the",
"major",
"difficulties",
"is",
"genetic",
"heterogeneity,",
"possibly",
"due",
"to",
"multiple,",
"incompletely",
"penetrant",
"PC-susceptibility",
"genes.",
"In",
"this",
"study,",
"we",
"explored",
"two",
"approaches",
"to",
"overcome",
"this",
"difficulty,",
"in",
"an",
"analysis",
"of",
"a",
"large",
"number",
"of",
"families",
"with",
"PC",
"in",
"the",
"International",
"Consortium",
"for",
"Prostate",
"Cancer",
"Genetics",
"(ICPCG).",
"One",
"approach",
"was",
"to",
"combine",
"linkage",
"data",
"from",
"a",
"total",
"of",
"1,233",
"families",
"to",
"increase",
"the",
"statistical",
"power",
"for",
"detecting",
"linkage.",
"Using",
"parametric",
"(dominant",
"and",
"recessive)",
"and",
"nonparametric",
"analyses,",
"we",
"identified",
"five",
"regions",
"with",
"\"suggestive\"",
"linkage",
"(LOD",
"score",
">1.86):",
"5q12,",
"8p21,",
"15q11,",
"17q21,",
"and",
"22q12.",
"The",
"second",
"approach",
"was",
"to",
"focus",
"on",
"subsets",
"of",
"families",
"that",
"are",
"more",
"likely",
"to",
"segregate",
"highly",
"penetrant",
"mutations,",
"including",
"families",
"with",
"large",
"numbers",
"of",
"affected",
"individuals",
"or",
"early",
"age",
"at",
"diagnosis.",
"Stronger",
"evidence",
"of",
"linkage",
"in",
"several",
"regions",
"was",
"identified,",
"including",
"a",
"\"significant\"",
"linkage",
"at",
"22q12,",
"with",
"a",
"LOD",
"score",
"of",
"3.57,",
"and",
"five",
"suggestive",
"linkages",
"(1q25,",
"8q13,",
"13q14,",
"16p13,",
"and",
"17q21)",
"in",
"269",
"families",
"with",
"at",
"least",
"five",
"affected",
"members.",
"In",
"addition,",
"four",
"additional",
"suggestive",
"linkages",
"(3p24,",
"5q35,",
"11q22,",
"and",
"Xq12)",
"were",
"found",
"in",
"606",
"families",
"with",
"mean",
"age",
"at",
"diagnosis",
"of",
"<",
"or",
"=",
"65",
"years.",
"Although",
"it",
"is",
"difficult",
"to",
"determine",
"the",
"true",
"statistical",
"significance",
"of",
"these",
"findings,",
"a",
"conservative",
"interpretation",
"of",
"these",
"results",
"would",
"be",
"that",
"if",
"major",
"PC-susceptibility",
"genes",
"do",
"exist,",
"they",
"are",
"most",
"likely",
"located",
"in",
"the",
"regions",
"generating",
"suggestive",
"or",
"significant",
"linkage",
"signals",
"in",
"this",
"large",
"study."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study. | [
2,
43,
4252,
3843,
7641,
8611,
4519,
1927,
21,
16,
19598,
5767,
1958,
5683,
2539,
17,
6461,
2628,
3609,
2007,
1920,
6019,
14056,
1958,
5683,
2539,
10072,
18,
3095,
1927,
1920,
8627,
1927,
3044,
5683,
2539,
12,
3808,
13,
17,
6461,
2628,
2258,
2252,
3675,
2007,
3137,
12707,
3247,
18,
2876,
3843,
7641,
15007,
2162,
2252,
2593,
1922,
2338,
43,
2608,
7490,
3484,
2351,
16,
3855,
9220,
3451,
2162,
2252,
7522,
2899,
1966,
3451,
1927,
4501,
18,
2340,
1927,
1920,
3044,
9097,
1977,
3299,
6808,
16,
6553,
2810,
1942,
3137,
16,
22504,
8126,
2031,
3808,
17,
6461,
2628,
18,
1922,
2052,
2161,
16,
2038,
7255,
2288,
4895,
1942,
9063,
2052,
8791,
16,
1922,
1925,
2333,
1927,
43,
3103,
2529,
1927,
5767,
1956,
3808,
1922,
1920,
6019,
14056,
1958,
5683,
2539,
10072,
12,
13215,
1030,
1029,
13,
18,
2340,
2998,
1982,
1942,
14003,
8611,
2230,
2037,
43,
2698,
1927,
21,
16,
19598,
5767,
1942,
2760,
1920,
3850,
4215,
1958,
9227,
8611,
18,
2193,
11848,
12,
6379,
1930,
13992,
13,
1930,
18991,
3247,
16,
2038,
2899,
3628,
3451,
1956,
6,
12855,
6,
8611,
12,
15187,
3593,
34,
21,
18,
5713,
13,
30,
25,
16886,
1028,
16,
28,
5991,
1009,
16,
2461,
23931,
16,
2752,
23470,
1009,
16,
1930,
2950,
16886,
1028,
18,
1920,
2812,
2998,
1982,
1942,
3691,
1990,
9524,
1927,
5767,
1988,
2032,
2253,
3205,
1942,
9762,
2010,
3626,
8126,
2031,
3527,
16,
2710,
5767,
1956,
3103,
4630,
1927,
4218,
3445,
2014,
3120,
2632,
2019,
3574,
18,
7926,
3095,
1927,
8611,
1922,
2980,
3451,
1982,
2899,
16,
2710,
43,
6,
2228,
6,
8611,
2019,
2950,
16886,
1028,
16,
1956,
43,
15187,
3593,
1927,
23,
18,
4786,
16,
1930,
3628,
12855,
19949,
12,
28798,
4198,
16,
28,
16886,
1010,
16,
2590,
16886,
1006,
16,
2641,
5113,
1010,
16,
1930,
2752,
23470,
1009,
13,
1922,
22843,
5767,
1956,
2019,
3464,
3628,
4218,
4678,
18,
1922,
2459,
16,
3006,
3281,
12855,
19949,
12,
11469,
4561,
16,
25,
1055,
5798,
16,
2513,
23470,
1028,
16,
1930,
66,
16886,
1028,
13,
1985,
2435,
1922,
3276,
1016,
5767,
1956,
2667,
2632,
2019,
3574,
1927,
32,
2014,
33,
4459,
2739,
18,
2876,
2176,
1977,
4571,
1942,
3415,
1920,
6228,
3850,
4550,
1927,
2144,
3056,
16,
43,
11375,
6332,
1927,
2144,
2274,
2962,
1998,
1988,
2647,
3044,
3808,
17,
6461,
2628,
2608,
5516,
16,
2611,
2032,
2501,
3205,
4810,
1922,
1920,
3451,
9155,
12855,
2014,
2228,
8611,
4771,
1922,
2052,
3103,
2161,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
11083946 | [
"The",
"28-kb",
"deletion",
"spanning",
"D15S63",
"is",
"a",
"polymorphic",
"variant",
"in",
"the",
"Ashkenazi",
"Jewish",
"population.",
"D15S63",
"is",
"one",
"of",
"the",
"loci,",
"on",
"chromosome",
"15q11-q13,",
"that",
"exhibit",
"parent-of-origin",
"dependent",
"methylation",
"and",
"that",
"is",
"commonly",
"used",
"in",
"the",
"diagnosis",
"of",
"Prader-Willi",
"or",
"Angelman",
"syndromes",
"(PWS/AS).",
"A",
"28-kb",
"deletion",
"spanning",
"the",
"D15S63",
"locus",
"was",
"identified",
"in",
"five",
"unrelated",
"patients;",
"in",
"each",
"of",
"them",
"the",
"deletion",
"was",
"inherited",
"from",
"a",
"normal",
"parent.",
"Three",
"of",
"the",
"five",
"families",
"segregating",
"the",
"deletion",
"were",
"reported",
"to",
"be",
"of",
"Jewish",
"Ashkenazi",
"ancestry,",
"and",
"in",
"the",
"other",
"two",
"families",
"the",
"ancestral",
"origin",
"was",
"unknown.",
"To",
"determine",
"whether",
"the",
"28-kb",
"deletion",
"is",
"a",
"benign",
"variant,",
"we",
"screened",
"for",
"the",
"deletion",
"in",
"137",
"unselected",
"Ashkenazi",
"individuals",
"and",
"in",
"268",
"patients",
"who",
"were",
"referred",
"for",
"molecular",
"diagnosis",
"of",
"PWS/AS,",
"of",
"whom",
"89",
"were",
"Ashkenazi",
"and",
"47",
"were",
"of",
"mixed",
"origin",
"(Ashkenazi",
"and",
"non-Ashkenazi",
"Jews).",
"In",
"the",
"control",
"group,",
"three",
"individuals",
"were",
"carriers",
"of",
"the",
"deletion;",
"among",
"the",
"patients,",
"three",
"were",
"carriers,",
"all",
"of",
"whom",
"were",
"Ashkenazi",
"Jews.",
"There",
"was",
"no",
"significant",
"difference",
"between",
"the",
"control",
"group",
"and",
"the",
"Ashkenazi",
"patients,",
"indicating",
"that",
"the",
"deletion",
"is",
"not",
"a",
"cause",
"of",
"PWS-",
"and",
"AS-like",
"syndromes.",
"The",
"frequency",
"of",
"the",
"28-kb",
"deletion",
"in",
"the",
"Ashkenazi",
"population",
"was",
"1/75.",
"Since",
"methylation",
"analysis",
"at",
"the",
"D15S63",
"locus",
"may",
"lead",
"to",
"misdiagnosis,",
"we",
"suggest",
"the",
"use",
"of",
"SNRPN,",
"either",
"in",
"a",
"PCR-based",
"assay",
"or",
"as",
"a",
"probe",
"in",
"Southern",
"hybridization,",
"as",
"the",
"method",
"of",
"choice",
"in",
"the",
"diagnosis",
"of",
"PWS/AS."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The 28-kb deletion spanning D15S63 is a polymorphic variant in the Ashkenazi Jewish population. D15S63 is one of the loci, on chromosome 15q11-q13, that exhibit parent-of-origin dependent methylation and that is commonly used in the diagnosis of Prader-Willi or Angelman syndromes (PWS/AS). A 28-kb deletion spanning the D15S63 locus was identified in five unrelated patients; in each of them the deletion was inherited from a normal parent. Three of the five families segregating the deletion were reported to be of Jewish Ashkenazi ancestry, and in the other two families the ancestral origin was unknown. To determine whether the 28-kb deletion is a benign variant, we screened for the deletion in 137 unselected Ashkenazi individuals and in 268 patients who were referred for molecular diagnosis of PWS/AS, of whom 89 were Ashkenazi and 47 were of mixed origin (Ashkenazi and non-Ashkenazi Jews). In the control group, three individuals were carriers of the deletion; among the patients, three were carriers, all of whom were Ashkenazi Jews. There was no significant difference between the control group and the Ashkenazi patients, indicating that the deletion is not a cause of PWS- and AS-like syndromes. The frequency of the 28-kb deletion in the Ashkenazi population was 1/75. Since methylation analysis at the D15S63 locus may lead to misdiagnosis, we suggest the use of SNRPN, either in a PCR-based assay or as a probe in Southern hybridization, as the method of choice in the diagnosis of PWS/AS. | [
2,
1920,
3158,
17,
6633,
5541,
13346,
8524,
1015,
22680,
1010,
1977,
43,
14240,
6031,
1922,
1920,
13696,
11341,
3408,
1033,
28296,
2471,
2973,
18,
8524,
1015,
22680,
1010,
1977,
2340,
1927,
1920,
6971,
16,
1990,
5597,
2461,
23931,
17,
22027,
1010,
16,
1988,
5987,
6162,
17,
1927,
17,
4853,
3100,
5547,
1930,
1988,
1977,
5384,
2251,
1922,
1920,
3574,
1927,
21227,
2179,
17,
13909,
2014,
29021,
3862,
12688,
12,
29314,
19,
1966,
13,
18,
43,
3158,
17,
6633,
5541,
13346,
1920,
8524,
1015,
22680,
1010,
6730,
1982,
2899,
1922,
3628,
10295,
2132,
31,
1922,
2362,
1927,
3581,
1920,
5541,
1982,
12911,
2037,
43,
2791,
6162,
18,
2559,
1927,
1920,
3628,
5767,
29185,
1920,
5541,
1985,
2568,
1942,
1998,
1927,
28296,
2471,
13696,
11341,
3408,
1033,
15419,
16,
1930,
1922,
1920,
2303,
2288,
5767,
1920,
14417,
4853,
1982,
5435,
18,
1942,
3415,
3053,
1920,
3158,
17,
6633,
5541,
1977,
43,
8867,
6031,
16,
2038,
8582,
1958,
1920,
5541,
1922,
11960,
27089,
13696,
11341,
3408,
1033,
3445,
1930,
1922,
22199,
2132,
2746,
1985,
6656,
1958,
3272,
3574,
1927,
29314,
19,
1966,
16,
1927,
8566,
5792,
1985,
13696,
11341,
3408,
1033,
1930,
4261,
1985,
1927,
4985,
4853,
12,
13696,
11341,
3408,
1033,
1930,
2447,
17,
13696,
11341,
3408,
1033,
28296,
1036,
13,
18,
1922,
1920,
2285,
2210,
16,
2559,
3445,
1985,
8974,
1927,
1920,
5541,
31,
2706,
1920,
2132,
16,
2559,
1985,
8974,
16,
2136,
1927,
8566,
1985,
13696,
11341,
3408,
1033,
28296,
1036,
18,
2276,
1982,
2239,
2228,
3175,
2192,
1920,
2285,
2210,
1930,
1920,
13696,
11341,
3408,
1033,
2132,
16,
4168,
1988,
1920,
5541,
1977,
2084,
43,
3936,
1927,
29314,
17,
1930,
1966,
17,
3189,
12688,
18,
1920,
3528,
1927,
1920,
3158,
17,
6633,
5541,
1922,
1920,
13696,
11341,
3408,
1033,
2973,
1982,
21,
19,
4089,
18,
3328,
5547,
2333,
2019,
1920,
8524,
1015,
22680,
1010,
6730,
2278,
2949,
1942,
23887,
2475,
16,
2038,
3220,
1920,
2485,
1927,
11970,
27257,
16,
3108,
1922,
43,
3343,
17,
2454,
3381,
2014,
1966,
43,
5598,
1922,
9257,
8335,
16,
1966,
1920,
2417,
1927,
6259,
1922,
1920,
3574,
1927,
29314,
19,
1966,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
15846561 | [
"Heterozygous",
"mutations",
"of",
"OTX2",
" ",
"cause",
"severe",
"ocular",
"malformations.",
"Major",
"malformations",
"of",
"the",
"human",
"eye,",
"including",
"microphthalmia",
"and",
"anophthalmia,",
"are",
"examples",
"of",
"phenotypes",
"that",
"recur",
"in",
"families",
"yet",
"often",
"show",
"no",
"clear",
"Mendelian",
"inheritance",
"pattern.",
"Defining",
"loci",
"by",
"mapping",
"is",
"therefore",
"rarely",
"feasible.",
"Using",
"a",
"candidate-gene",
"approach,",
"we",
"have",
"identified",
"heterozygous",
"coding-region",
"changes",
"in",
"the",
"homeobox",
"gene",
"OTX2",
" ",
"in",
"eight",
"families",
"with",
"ocular",
"malformations.",
"The",
"expression",
"pattern",
"of",
"OTX2",
" ",
"in",
"human",
"embryos",
"is",
"consistent",
"with",
"the",
"eye",
"phenotypes",
"observed",
"in",
"the",
"patients,",
"which",
"range",
"from",
"bilateral",
"anophthalmia",
"to",
"retinal",
"defects",
"resembling",
"Leber",
"congenital",
"amaurosis",
"and",
"pigmentary",
"retinopathy.",
"Magnetic",
"resonance",
"imaging",
"scans",
"revealed",
"defects",
"of",
"the",
"optic",
"nerve,",
"optic",
"chiasm,",
"and,",
"in",
"some",
"cases,",
"brain.",
"In",
"two",
"families,",
"the",
"mutations",
"appear",
"to",
"have",
"occurred",
"de",
"novo",
"in",
"severely",
"affected",
"offspring,",
"and,",
"in",
"two",
"other",
"families,",
"the",
"mutations",
"have",
"been",
"inherited",
"from",
"a",
"gonosomal",
"mosaic",
"parent.",
"Data",
"from",
"these",
"four",
"families",
"support",
"a",
"simple",
"model",
"in",
"which",
"OTX2",
" ",
"heterozygous",
"loss-of-function",
"mutations",
"cause",
"ocular",
"malformations.",
"Four",
"additional",
"families",
"display",
"complex",
"inheritance",
"patterns,",
"suggesting",
"that",
"OTX2",
" ",
"mutations",
"alone",
"may",
"not",
"lead",
"to",
"consistent",
"phenotypes.",
"The",
"high",
"incidence",
"of",
"mosaicism",
"and",
"the",
"reduced",
"penetrance",
"have",
"implications",
"for",
"genetic",
"counseling."
] | [
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Heterozygous mutations of OTX2 cause severe ocular malformations. Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling. | [
2,
9589,
3527,
1927,
7608,
8014,
3936,
4010,
10046,
17360,
18,
3044,
17360,
1927,
1920,
2616,
5723,
16,
2710,
18274,
19253,
7289,
6026,
1930,
21969,
27980,
2126,
16,
2032,
7604,
1927,
6568,
1988,
2090,
1949,
1922,
5767,
4898,
3868,
2146,
2239,
4021,
22702,
15762,
3114,
18,
11266,
6971,
2007,
7084,
1977,
2955,
9671,
9730,
18,
2193,
43,
6610,
17,
2359,
2998,
16,
2038,
2162,
2899,
9589,
5804,
17,
3031,
2840,
1922,
1920,
27566,
2359,
7608,
8014,
1922,
5066,
5767,
1956,
10046,
17360,
18,
1920,
2294,
3114,
1927,
7608,
8014,
1922,
2616,
6274,
1977,
3499,
1956,
1920,
5723,
6568,
2528,
1922,
1920,
2132,
16,
2154,
3109,
2037,
7787,
21969,
27980,
2126,
1942,
6943,
6007,
18994,
2071,
2361,
9901,
2150,
6346,
4870,
1930,
12905,
2141,
15508,
18,
5691,
6912,
3755,
8581,
3404,
6007,
1927,
1920,
10109,
5507,
16,
10109,
7368,
2691,
16,
1930,
16,
1922,
2673,
2919,
16,
3068,
18,
1922,
2288,
5767,
16,
1920,
3527,
3267,
1942,
2162,
4807,
2028,
9441,
1922,
10561,
4218,
9074,
16,
1930,
16,
1922,
2288,
2303,
5767,
16,
1920,
3527,
2162,
2252,
12911,
2037,
43,
8239,
4969,
15605,
6162,
18,
2230,
2037,
2144,
3006,
5767,
3373,
43,
5288,
2322,
1922,
2154,
7608,
8014,
9589,
3257,
17,
1927,
17,
2347,
3527,
3936,
10046,
17360,
18,
3006,
3281,
5767,
4434,
2796,
15762,
4147,
16,
3783,
1988,
7608,
8014,
3527,
4298,
2278,
2084,
2949,
1942,
3499,
6568,
18,
1920,
2149,
4332,
1927,
15605,
2421,
1930,
1920,
3028,
22035,
2162,
7020,
1958,
3299,
12239,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
7825598 | [
"Evidence",
"for",
"an",
"association",
"between",
"RFLPs",
"at",
"the",
"transforming",
"growth",
"factor",
"alpha",
"(locus)",
"and",
"nonsyndromic",
"cleft",
"lip/palate",
"in",
"a",
"South",
"American",
"population."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Evidence for an association between RFLPs at the transforming growth factor alpha (locus) and nonsyndromic cleft lip/palate in a South American population. | [
2,
3095,
1958,
1925,
3279,
2192,
22393,
1036,
2019,
1920,
13231,
2905,
2991,
4595,
12,
6730,
13,
1930,
23428,
3883,
3264,
14649,
3178,
19,
19471,
1922,
43,
6061,
5339,
2973,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
15338459 | [
"\"Bias",
"toward",
"the",
"null\"",
"means",
"reduced",
"power."
] | [
0,
0,
0,
0,
0,
0,
0
] | "Bias toward the null" means reduced power. | [
2,
6,
5353,
4205,
1920,
6764,
6,
4457,
3028,
4215,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9792853 | [
"Development",
"and",
"maintenance",
"of",
"ear",
"innervation",
"and",
"function:",
"lessons",
"from",
"mutations",
"in",
"mouse",
"and",
"man."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Development and maintenance of ear innervation and function: lessons from mutations in mouse and man. | [
2,
2740,
1930,
6291,
1927,
4352,
19099,
1930,
2347,
30,
20789,
2037,
3527,
1922,
3321,
1930,
2323,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
11793480 | [
"BRCA1",
" ",
"and",
"BRCA2",
" ",
"mutations",
"in",
"Russian",
"familial",
"breast",
"cancer.",
"We",
"have",
"screened",
"index",
"cases",
"from",
"25",
"Russian",
"breast/ovarian",
"cancer",
"families",
"for",
"germ-line",
"mutations",
"in",
"all",
"coding",
"exons",
"of",
"the",
"BRCA1",
" ",
"and",
"BRCA2",
" ",
"genes,",
"using",
"multiplex",
"heteroduplex",
"analysis.",
"In",
"addition",
"we",
"tested",
"22",
"patients",
"with",
"breast",
"cancer",
"diagnosed",
"before",
"age",
"40",
"without",
"family",
"history",
"and",
"6",
"patients",
"with",
"bilateral",
"breast",
"cancer.",
"The",
"frequency",
"of",
"families",
"with",
"germline",
"mutations",
"in",
"BRCA",
"was",
"16%",
"(4/25).",
"One",
"BRCA1",
" ",
"mutation,",
"5382insC",
",",
"was",
"found",
"in",
"three",
"families.",
"The",
"results",
"of",
"present",
"study,",
"and",
"those",
"of",
"a",
"separate",
"study",
"of",
"19",
"breast-ovarian",
"cancer",
"families,",
"suggest",
"that",
"BRCA1",
" ",
"5382insC",
" ",
"is",
"a",
"founder",
"mutation",
"in",
"the",
"Russian",
"population.",
"Three",
"BRCA2",
" ",
"mutations",
"were",
"found",
"in",
"patients",
"with",
"breast",
"cancer",
"without",
"family",
"history:",
"two",
"in",
"young",
"patients",
"and",
"one",
"in",
"patients",
"with",
"bilateral",
"breast",
"cancer.",
"Four",
"novel",
"BRCA2",
" ",
"mutations",
"were",
"identified:",
"three",
"frameshift",
"(",
"695insT",
",",
"1528del4",
",",
"9318del4",
")",
"and",
"one",
"nonsense",
"(",
"S1099X",
")."
] | [
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
0,
0,
0,
0,
3,
0
] | BRCA1 and BRCA2 mutations in Russian familial breast cancer. We have screened index cases from 25 Russian breast/ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using multiplex heteroduplex analysis. In addition we tested 22 patients with breast cancer diagnosed before age 40 without family history and 6 patients with bilateral breast cancer. The frequency of families with germline mutations in BRCA was 16% (4/25). One BRCA1 mutation, 5382insC , was found in three families. The results of present study, and those of a separate study of 19 breast-ovarian cancer families, suggest that BRCA1 5382insC is a founder mutation in the Russian population. Three BRCA2 mutations were found in patients with breast cancer without family history: two in young patients and one in patients with bilateral breast cancer. Four novel BRCA2 mutations were identified: three frameshift ( 695insT , 1528del4 , 9318del4 ) and one nonsense ( S1099X ). | [
2,
11779,
1930,
17845,
3527,
1922,
26012,
11444,
3739,
2539,
18,
2038,
2162,
8582,
3867,
2919,
2037,
2637,
26012,
3739,
19,
6751,
2539,
5767,
1958,
4363,
17,
2823,
3527,
1922,
2136,
5804,
10419,
1927,
1920,
11779,
1930,
17845,
2628,
16,
2193,
12710,
11330,
3481,
2592,
2333,
18,
1922,
2459,
2038,
3620,
2950,
2132,
1956,
3739,
2539,
5377,
3119,
2632,
3040,
2979,
3416,
4403,
1930,
26,
2132,
1956,
7787,
3739,
2539,
18,
1920,
3528,
1927,
5767,
1956,
12237,
3527,
1922,
9236,
1982,
2641,
9,
12,
24,
19,
2637,
13,
18,
2340,
11779,
3979,
16,
4522,
11715,
2925,
1030,
16,
1982,
2435,
1922,
2559,
5767,
18,
1920,
2274,
1927,
2481,
2161,
16,
1930,
2690,
1927,
43,
5850,
2161,
1927,
2282,
3739,
17,
6751,
2539,
5767,
16,
3220,
1988,
11779,
4522,
11715,
2925,
1030,
1977,
43,
21350,
3979,
1922,
1920,
26012,
2973,
18,
2559,
17845,
3527,
1985,
2435,
1922,
2132,
1956,
3739,
2539,
2979,
3416,
4403,
30,
2288,
1922,
4201,
2132,
1930,
2340,
1922,
2132,
1956,
7787,
3739,
2539,
18,
3006,
4008,
17845,
3527,
1985,
2899,
30,
2559,
21848,
12,
5349,
1015,
2925,
1031,
16,
14039,
1025,
16878,
1006,
16,
6156,
3928,
16878,
1006,
13,
1930,
2340,
19605,
12,
16775,
6576,
1039,
13,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
0,
3,
4,
4,
4,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
-100
] |
17999359 | [
"RAD51",
" ",
"135G-->C",
" ",
"modifies",
"breast",
"cancer",
"risk",
"among",
"BRCA2",
" ",
"mutation",
"carriers:",
"results",
"from",
"a",
"combined",
"analysis",
"of",
"19",
"studies.",
"RAD51",
" ",
"is",
"an",
"important",
"component",
"of",
"double-stranded",
"DNA-repair",
"mechanisms",
"that",
"interacts",
"with",
"both",
"BRCA1",
" ",
"and",
"BRCA2",
".",
"A",
"single-nucleotide",
"polymorphism",
"(SNP)",
"in",
"the",
"5'",
"untranslated",
"region",
"(UTR)",
"of",
"RAD51",
",",
"135G-->C,",
"has",
"been",
"suggested",
"as",
"a",
"possible",
"modifier",
"of",
"breast",
"cancer",
"risk",
"in",
"BRCA1",
" ",
"and",
"BRCA2",
" ",
"mutation",
"carriers.",
"We",
"pooled",
"genotype",
"data",
"for",
"8,512",
"female",
"mutation",
"carriers",
"from",
"19",
"studies",
"for",
"the",
"RAD51",
" ",
"135G-->C",
" ",
"SNP.",
"We",
"found",
"evidence",
"of",
"an",
"increased",
"breast",
"cancer",
"risk",
"in",
"CC",
"homozygotes",
"(hazard",
"ratio",
"[HR]",
"1.92",
"[95%",
"confidence",
"interval",
"{CI}",
"1.25-2.94)",
"but",
"not",
"in",
"heterozygotes",
"(HR",
"0.95",
"[95%",
"CI",
"0.83-1.07];",
"P=.002,",
"by",
"heterogeneity",
"test",
"with",
"2",
"degrees",
"of",
"freedom",
"[df]).",
"When",
"BRCA1",
" ",
"and",
"BRCA2",
" ",
"mutation",
"carriers",
"were",
"analyzed",
"separately,",
"the",
"increased",
"risk",
"was",
"statistically",
"significant",
"only",
"among",
"BRCA2",
" ",
"mutation",
"carriers,",
"in",
"whom",
"we",
"observed",
"HRs",
"of",
"1.17",
"(95%",
"CI",
"0.91-1.51)",
"among",
"heterozygotes",
"and",
"3.18",
"(95%",
"CI",
"1.39-7.27)",
"among",
"rare",
"homozygotes",
"(P=.0007,",
"by",
"heterogeneity",
"test",
"with",
"2",
"df).",
"In",
"addition,",
"we",
"determined",
"that",
"the",
"135G-->C",
" ",
"variant",
"affects",
"RAD51",
" ",
"splicing",
"within",
"the",
"5'",
"UTR.",
"Thus,",
"135G-->C",
" ",
"may",
"modify",
"the",
"risk",
"of",
"breast",
"cancer",
"in",
"BRCA2",
" ",
"mutation",
"carriers",
"by",
"altering",
"the",
"expression",
"of",
"RAD51",
".",
"RAD51",
"is",
"the",
"first",
"gene",
"to",
"be",
"reliably",
"identified",
"as",
"a",
"modifier",
"of",
"risk",
"among",
"BRCA1/2",
"RAD51",
"135G-->C",
",",
"has",
"been",
"suggested",
"as",
"a",
"possible",
"modifier",
"of",
"breast",
"cancer",
"risk",
"in",
"BRCA1",
"and",
"BRCA2",
"mutation",
"carriers.",
"We",
"pooled",
"genotype",
"data",
"for",
"8,512",
"female",
"mutation",
"carriers",
"from",
"19",
"studies",
"for",
"the",
"RAD51",
"135G-->C",
"SNP.",
"We",
"found",
"evidence",
"of",
"an",
"increased",
"breast",
"cancer",
"risk",
"in",
"CC",
"homozygotes",
"(hazard",
"ratio",
"[HR]",
"1.92",
"[95%",
"confidence",
"interval",
"{CI}",
"1.25-2.94)",
"but",
"not",
"in",
"heterozygotes",
"(HR",
"0.95",
"[95%",
"CI",
"0.83-1.07];",
"P=.002,",
"by",
"heterogeneity",
"test",
"with",
"2",
"degrees",
"of",
"freedom",
"[df]).",
"When",
"BRCA1",
"and",
"BRCA2",
"mutation",
"carriers",
"were",
"analyzed",
"separately,",
"the",
"increased",
"risk",
"was",
"statistically",
"significant",
"only",
"among",
"BRCA2",
"mutation",
"carriers,",
"in",
"whom",
"we",
"observed",
"HRs",
"of",
"1.17",
"(95%",
"CI",
"0.91-1.51)",
"among",
"heterozygotes",
"and",
"3.18",
"(95%",
"CI",
"1.39-7.27)",
"among",
"rare",
"homozygotes",
"(P=.0007,",
"by",
"heterogeneity",
"test",
"with",
"2",
"df).",
"In",
"addition,",
"we",
"determined",
"that",
"the",
"135G-->C",
"variant",
"affects",
"RAD51",
"splicing",
"within",
"the",
"5'",
"UTR.",
"Thus,",
"135G-->C",
"may",
"modify",
"the",
"risk",
"of",
"breast",
"cancer",
"in",
"BRCA2",
"mutation",
"carriers",
"by",
"altering",
"the",
"expression",
"of",
"RAD51.",
"RAD51",
"is",
"the",
"first",
"gene",
"to",
"be",
"reliably",
"identified",
"as",
"a",
"modifier",
"of",
"risk",
"among",
"BRCA1/2",
"mutation",
"carriers."
] | [
1,
0,
3,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2 . A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51 , 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51 . RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 RAD51 135G-->C , has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers. | [
2,
15897,
11477,
1029,
17,
17,
34,
45,
25436,
3739,
2539,
2565,
2706,
17845,
3979,
8974,
30,
2274,
2037,
43,
4252,
2333,
1927,
2282,
2351,
18,
15897,
1977,
1925,
2715,
4594,
1927,
4825,
17,
10338,
2678,
17,
5059,
3531,
1988,
9034,
1956,
2321,
11779,
1930,
17845,
18,
43,
2957,
17,
5489,
8218,
12,
6821,
13,
1922,
1920,
25,
11,
19522,
3031,
12,
8812,
13,
1927,
15897,
16,
11477,
1029,
17,
17,
34,
45,
16,
2258,
2252,
3978,
1966,
43,
3216,
22883,
1927,
3739,
2539,
2565,
1922,
11779,
1930,
17845,
3979,
8974,
18,
2038,
7803,
5619,
2230,
1958,
28,
16,
20094,
4232,
3979,
8974,
2037,
2282,
2351,
1958,
1920,
15897,
11477,
1029,
17,
17,
34,
45,
6821,
18,
2038,
2435,
3095,
1927,
1925,
2502,
3739,
2539,
2565,
1922,
4928,
22686,
12,
7320,
3400,
37,
3668,
39,
21,
18,
6224,
37,
3002,
9,
5203,
4979,
69,
3371,
71,
21,
18,
2637,
17,
22,
18,
5650,
13,
2308,
2084,
1922,
22910,
12,
3668,
20,
18,
3002,
37,
3002,
9,
3371,
20,
18,
5893,
17,
21,
18,
6627,
39,
31,
58,
33,
18,
9299,
16,
2007,
6808,
2648,
1956,
22,
6429,
1927,
13435,
37,
8122,
39,
13,
18,
2469,
11779,
1930,
17845,
3979,
8974,
1985,
3265,
7555,
16,
1920,
2502,
2565,
1982,
4388,
2228,
2444,
2706,
17845,
3979,
8974,
16,
1922,
8566,
2038,
2528,
10079,
1927,
21,
18,
2752,
12,
3002,
9,
3371,
20,
18,
6550,
17,
21,
18,
4892,
13,
2706,
22910,
1930,
23,
18,
2654,
12,
3002,
9,
3371,
21,
18,
3886,
17,
27,
18,
3225,
13,
2706,
5844,
22686,
12,
58,
33,
18,
3240,
1027,
16,
2007,
6808,
2648,
1956,
22,
8122,
13,
18,
1922,
2459,
16,
2038,
3180,
1988,
1920,
11477,
1029,
17,
17,
34,
45,
6031,
6886,
15897,
8490,
2651,
1920,
25,
11,
8812,
18,
2842,
16,
11477,
1029,
17,
17,
34,
45,
2278,
11675,
1920,
2565,
1927,
3739,
2539,
1922,
17845,
3979,
8974,
2007,
12571,
1920,
2294,
1927,
15897,
18,
15897,
1977,
1920,
2561,
2359,
1942,
1998,
13445,
2899,
1966,
43,
22883,
1927,
2565,
2706,
11779,
19,
22,
15897,
11477,
1029,
17,
17,
34,
45,
16,
2258,
2252,
3978,
1966,
43,
3216,
22883,
1927,
3739,
2539,
2565,
1922,
11779,
1930,
17845,
3979,
8974,
18,
2038,
7803,
5619,
2230,
1958,
28,
16,
20094,
4232,
3979,
8974,
2037,
2282,
2351,
1958,
1920,
15897,
11477,
1029,
17,
17,
34,
45,
6821,
18,
2038,
2435,
3095,
1927,
1925,
2502,
3739,
2539,
2565,
1922,
4928,
22686,
12,
7320,
3400,
37,
3668,
39,
21,
18,
6224,
37,
3002,
9,
5203,
4979,
69,
3371,
71,
21,
18,
2637,
17,
22,
18,
5650,
13,
2308,
2084,
1922,
22910,
12,
3668,
20,
18,
3002,
37,
3002,
9,
3371,
20,
18,
5893,
17,
21,
18,
6627,
39,
31,
58,
33,
18,
9299,
16,
2007,
6808,
2648,
1956,
22,
6429,
1927,
13435,
37,
8122,
39,
13,
18,
2469,
11779,
1930,
17845,
3979,
8974,
1985,
3265,
7555,
16,
1920,
2502,
2565,
1982,
4388,
2228,
2444,
2706,
17845,
3979,
8974,
16,
1922,
8566,
2038,
2528,
10079,
1927,
21,
18,
2752,
12,
3002,
9,
3371,
20,
18,
6550,
17,
21,
18,
4892,
13,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
1,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9382097 | [
"Neonatal,",
"lethal",
"noncompaction",
"of",
"the",
"left",
"ventricular",
"myocardium",
"is",
"allelic",
"with",
"Barth",
"syndrome.",
"Loss-of-function",
"mutations",
"in",
"the",
"G4.5",
"gene",
"have",
"been",
"shown",
"to",
"cause",
"Barth",
"syndrome",
"(BTHS),",
"an",
"X-linked",
"disorder",
"characterized",
"by",
"cardiac",
"and",
"skeletal",
"myopathy,",
"short",
"stature,",
"and",
"neutropenia.",
"We",
"recently",
"reported",
"a",
"family",
"with",
"a",
"severe",
"X-linked",
"cardiomyopathy",
"described",
"as",
"isolated",
"noncompaction",
"of",
"the",
"left",
"ventricular",
"myocardium",
"(INVM).",
"Other",
"findings",
"associated",
"with",
"BTHS",
"(skeletal",
"myopathy,",
"neutropenia,",
"growth",
"retardation,",
"elevated",
"urinary",
"organic",
"acids,",
"and",
"mitochondrial",
"abnormalities)",
"were",
"either",
"absent",
"or",
"inconsistent.",
"A",
"linkage",
"study",
"of",
"the",
"X",
"chromosome",
"localized",
"INVM",
"to",
"the",
"Xq28",
"region",
"near",
"the",
"BTHS",
"locus,",
"suggesting",
"that",
"these",
"disorders",
"are",
"allelic.",
"We",
"screened",
"the",
"G4.5",
" ",
"gene",
"for",
"mutations",
"in",
"this",
"family",
"with",
"SSCP",
"and",
"direct",
"sequencing",
"and",
"found",
"a",
"novel",
"glycine-to-arginine",
"substitution",
"at",
"position",
"197.",
"This",
"position",
"is",
"conserved",
"in",
"a",
"homologous",
"Caenorhabditis",
"elegans",
"protein.",
"We",
"conclude",
"that",
"INVM",
"is",
"a",
"severe",
"allelic",
"variant",
"of",
"BTHS",
"with",
"a",
"specific",
"effect",
"on",
"the",
"heart.",
"This",
"finding",
"provides",
"further",
"structure-function",
"information",
"about",
"the",
"G4.5",
"glycine-to-arginine",
"substitution",
"at",
"position",
"197",
".",
"This",
"position",
"is",
"conserved",
"in",
"a",
"homologous",
"Caenorhabditis",
"elegans",
"protein.",
"We",
"conclude",
"that",
"INVM",
"is",
"a",
"severe",
"allelic",
"variant",
"of",
"BTHS",
"with",
"a",
"specific",
"effect",
"on",
"the",
"heart.",
"This",
"finding",
"provides",
"further",
"structure-function",
"information",
"about",
"the",
"G4.5",
"gene",
"product",
"and",
"has",
"implications",
"for",
"unexplained",
"cases",
"of",
"severe",
"infantile",
"hypertrophic",
"cardiomyopathy",
"in",
"males."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome. Loss-of-function mutations in the G4.5 gene have been shown to cause Barth syndrome (BTHS), an X-linked disorder characterized by cardiac and skeletal myopathy, short stature, and neutropenia. We recently reported a family with a severe X-linked cardiomyopathy described as isolated noncompaction of the left ventricular myocardium (INVM). Other findings associated with BTHS (skeletal myopathy, neutropenia, growth retardation, elevated urinary organic acids, and mitochondrial abnormalities) were either absent or inconsistent. A linkage study of the X chromosome localized INVM to the Xq28 region near the BTHS locus, suggesting that these disorders are allelic. We screened the G4.5 gene for mutations in this family with SSCP and direct sequencing and found a novel glycine-to-arginine substitution at position 197. This position is conserved in a homologous Caenorhabditis elegans protein. We conclude that INVM is a severe allelic variant of BTHS with a specific effect on the heart. This finding provides further structure-function information about the G4.5 glycine-to-arginine substitution at position 197 . This position is conserved in a homologous Caenorhabditis elegans protein. We conclude that INVM is a severe allelic variant of BTHS with a specific effect on the heart. This finding provides further structure-function information about the G4.5 gene product and has implications for unexplained cases of severe infantile hypertrophic cardiomyopathy in males. | [
2,
7985,
16,
10470,
22849,
4302,
2236,
1927,
1920,
3506,
6493,
13295,
1977,
13045,
1956,
30209,
4741,
18,
3257,
17,
1927,
17,
2347,
3527,
1922,
1920,
14036,
18,
25,
2359,
2162,
2252,
2522,
1942,
3936,
30209,
4741,
12,
8626,
8092,
13,
16,
1925,
66,
17,
4624,
4770,
4378,
2007,
4435,
1930,
7345,
25017,
16,
3662,
25906,
16,
1930,
18005,
18,
2038,
3998,
2568,
43,
3416,
1956,
43,
4010,
66,
17,
4624,
14141,
2910,
1966,
3937,
22849,
4302,
2236,
1927,
1920,
3506,
6493,
13295,
12,
2269,
1035,
13,
18,
2303,
3056,
2458,
1956,
8626,
8092,
12,
7345,
25017,
16,
18005,
16,
2905,
16342,
16,
4664,
7075,
6805,
4576,
16,
1930,
4596,
6754,
13,
1985,
3108,
7685,
2014,
12061,
18,
43,
8611,
2161,
1927,
1920,
66,
5597,
6579,
2269,
1035,
1942,
1920,
66,
23470,
1025,
3031,
4931,
1920,
8626,
8092,
6730,
16,
3783,
1988,
2144,
4414,
2032,
13045,
18,
2038,
8582,
1920,
14036,
18,
25,
2359,
1958,
3527,
1922,
2052,
3416,
1956,
13061,
1034,
1930,
3083,
4754,
1930,
2435,
43,
4008,
10646,
17,
1942,
17,
9732,
6636,
2019,
3507,
5876,
18,
2052,
3507,
1977,
5305,
1922,
43,
8725,
22418,
10861,
2213,
18,
2038,
7676,
1988,
2269,
1035,
1977,
43,
4010,
13045,
6031,
1927,
8626,
8092,
1956,
43,
2487,
2495,
1990,
1920,
4003,
18,
2052,
2849,
4558,
2520,
3170,
17,
2347,
2988,
3001,
1920,
14036,
18,
25,
10646,
17,
1942,
17,
9732,
6636,
2019,
3507,
5876,
18,
2052,
3507,
1977,
5305,
1922,
43,
8725,
22418,
10861,
2213,
18,
2038,
7676,
1988,
2269,
1035,
1977,
43,
4010,
13045,
6031,
1927,
8626,
8092,
1956,
43,
2487,
2495,
1990,
1920,
4003,
18,
2052,
2849,
4558,
2520,
3170,
17,
2347,
2988,
3001,
1920,
14036,
18,
25,
2359,
4863,
1930,
2258,
7020,
1958,
21109,
2919,
1927,
4010,
26975,
17437,
14141,
1922,
5129,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1415242 | [
"A",
"problem-based",
"learning",
"approach",
"to",
"teaching",
"medical",
"genetics.",
"A",
"newly",
"developed",
"problem-based",
"medical",
"genetics",
"course",
"that",
"was",
"integrated",
"into",
"the",
"fourth-year",
"medical",
"school",
"curriculum",
"of",
"the",
"University",
"of",
"Texas",
"Health",
"Science",
"Center",
"at",
"San",
"Antonio",
"is",
"described.",
"To",
"provide",
"a",
"basic",
"genetic",
"background",
"for",
"the",
"clinical",
"rotations,",
"a",
"supplemental",
"computer",
"tutorial",
"is",
"required",
"during",
"the",
"second",
"year.",
"These",
"two",
"formats",
"prepare",
"the",
"medical",
"students",
"to",
"recognize",
"genetic",
"diseases,",
"to",
"provide",
"basic",
"genetic",
"counseling",
"in",
"their",
"daily",
"practice,",
"and",
"to",
"appropriately",
"refer",
"patients",
"to",
"genetic",
"specialists."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A problem-based learning approach to teaching medical genetics. A newly developed problem-based medical genetics course that was integrated into the fourth-year medical school curriculum of the University of Texas Health Science Center at San Antonio is described. To provide a basic genetic background for the clinical rotations, a supplemental computer tutorial is required during the second year. These two formats prepare the medical students to recognize genetic diseases, to provide basic genetic counseling in their daily practice, and to appropriately refer patients to genetic specialists. | [
2,
43,
4915,
17,
2454,
4809,
2998,
1942,
10655,
3423,
10072,
18,
43,
7471,
3530,
4915,
17,
2454,
3423,
10072,
4914,
1988,
1982,
6714,
2460,
1920,
8776,
17,
2476,
3423,
5097,
15818,
1927,
1920,
3926,
1927,
14477,
2436,
5530,
4102,
2019,
6867,
25327,
3940,
1977,
2910,
18,
1942,
3394,
43,
5937,
3299,
3872,
1958,
1920,
2535,
22737,
16,
43,
6442,
7058,
21260,
17145,
1977,
3414,
2409,
1920,
2812,
2476,
18,
2144,
2288,
21950,
12674,
1920,
3423,
5187,
1942,
9967,
3299,
3902,
16,
1942,
3394,
5937,
3299,
12239,
1922,
2310,
4692,
4695,
16,
1930,
1942,
14221,
3333,
2132,
1942,
3299,
15992,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8304350 | [
"Apolipoprotein",
"E",
" ",
"polymorphism",
"influences",
"postprandial",
"retinyl",
"palmitate",
"but",
"not",
"triglyceride",
"concentrations.",
"To",
"quantify",
"the",
"effect",
"of",
"the",
"apolipoprotein",
"(apo)",
"E",
" ",
"polymorphism",
"on",
"the",
"magnitude",
"of",
"postprandial",
"lipemia,",
"we",
"have",
"defined",
"its",
"role",
"in",
"determining",
"the",
"response",
"to",
"a",
"single",
"high-fat",
"meal",
"in",
"a",
"large",
"sample",
"of",
"(N",
"=",
"474)",
"individuals",
"taking",
"part",
"in",
"the",
"biethnic",
"Atherosclerosis",
"Risk",
"in",
"Communities",
"Study.",
"The",
"profile",
"of",
"postprandial",
"response",
"in",
"plasma",
"was",
"monitored",
"over",
"8",
"h",
"by",
"triglyceride,",
"triglyceride-rich",
"lipoprotein",
"(TGRL)-triglyceride",
",",
"apo",
"B-48/apo",
"B-100",
"ratio,",
"and",
"retinyl",
"palmitate",
"concentrations,",
"and",
"the",
"apo",
"E",
" ",
"polymorphism",
"was",
"determined",
"by",
"DNA",
"amplification",
"and",
"digestion.",
"The",
"frequency",
"of",
"the",
"apo",
"E",
"alleles",
"and",
"their",
"effects",
"on",
"fasting",
"lipid",
"levels",
"in",
"this",
"sample",
"were",
"similar",
"to",
"those",
"reported",
"elsewhere.",
"Postprandial",
"plasma",
"retinyl",
"palmitate",
"response",
"to",
"a",
"high-fat",
"meal",
"with",
"vitamin",
"A",
"was",
"significantly",
"different",
"among",
"apo",
"E",
"genotypes,",
"with",
"delayed",
"clearance",
"in",
"individuals",
"with",
"an",
"epsilon",
"2",
"allele,",
"compared",
"with",
"epsilon",
"3/3",
"and",
"epsilon",
"3/4",
"individuals.",
"In",
"the",
"sample",
"of",
"397",
"Caucasians,",
"average",
"retinyl",
"palmitate",
"response",
"was",
"1,489",
"micrograms/dl",
"in",
"epsilon",
"2/3",
"individuals,",
"compared",
"with",
"1,037",
"micrograms/dl",
"in",
"epsilon",
"3/3",
"individuals",
"and",
"1,108",
"micrograms/dl",
"in",
"epsilon",
"3/4",
"individuals.",
"The",
"apo",
"E",
"polymorphism",
"accounted",
"for",
"7.1%",
"of",
"the",
"interindividual",
"variation",
"in",
"postprandial",
"retinyl",
"palmitate",
"response,",
"a",
"contribution",
"proportionally",
"greater",
"than",
"its",
"well-known",
"effect",
"on",
"fasting",
"LDL-cholesterol.",
"However,",
"despite",
"this",
"effect",
"on",
"postprandial",
"retinyl",
"palmitate,",
"the",
"profile",
"of",
"postprandial",
"triglyceride",
"response",
"was",
"not",
"significantly",
"different",
"among",
"apo",
"E",
"apo",
"E",
"apo",
"E",
"apo",
"E",
" ",
"alleles",
"and",
"their",
"effects",
"on",
"fasting",
"lipid",
"levels",
"in",
"this",
"sample",
"were",
"similar",
"to",
"those",
"reported",
"elsewhere.",
"Postprandial",
"plasma",
"retinyl",
"palmitate",
"response",
"to",
"a",
"high-fat",
"meal",
"with",
"vitamin",
"A",
"was",
"significantly",
"different",
"among",
"apo",
"E",
"genotypes,",
"with",
"delayed",
"clearance",
"in",
"individuals",
"with",
"an",
"epsilon",
"2",
"allele,",
"compared",
"with",
"epsilon",
"3/3",
"and",
"epsilon",
"3/4",
"individuals.",
"In",
"the",
"sample",
"of",
"397",
"Caucasians,",
"average",
"retinyl",
"palmitate",
"response",
"was",
"1,489",
"micrograms/dl",
"in",
"epsilon",
"2/3",
"individuals,",
"compared",
"with",
"1,037",
"micrograms/dl",
"in",
"epsilon",
"3/3",
"individuals",
"and",
"1,108",
"micrograms/dl",
"in",
"epsilon",
"3/4",
"individuals.",
"The",
"apo",
"E",
"polymorphism",
"accounted",
"for",
"7.1%",
"of",
"the",
"interindividual",
"variation",
"in",
"postprandial",
"retinyl",
"palmitate",
"response,",
"a",
"contribution",
"proportionally",
"greater",
"than",
"its",
"well-known",
"effect",
"on",
"fasting",
"LDL-cholesterol.",
"However,",
"despite",
"this",
"effect",
"on",
"postprandial",
"retinyl",
"palmitate,",
"the",
"profile",
"of",
"postprandial",
"triglyceride",
"response",
"was",
"not",
"significantly",
"different",
"among",
"apo",
"E",
"genotypes.",
"The",
"profile",
"of",
"postprandial",
"response",
"was",
"consistent",
"between",
"the",
"sample",
"of",
"Caucasians",
"and",
"a",
"smaller",
"sample",
"of",
"black",
"subjects.",
"While",
"these",
"data",
"indicate",
"that",
"the",
"removal",
"of",
"remnant",
"particles",
"from",
"circulation",
"is",
"delayed",
"in",
"subjects",
"with",
"the",
"epsilon",
"2/3",
"genotype,",
"there",
"is",
"no",
"reported",
"evidence",
"that",
"the",
"epsilon",
"2",
"allele",
"predisposes",
"to",
"coronary",
"artery",
"disease",
"(CAD).",
"The",
"results",
"of",
"this",
"study",
"provide",
"not",
"only",
"a",
"reliable",
"estimate",
"of",
"the",
"magnitude",
"of",
"the",
"effect",
"of",
"the",
"apo",
"E",
" ",
"polymorphism",
"on",
"various",
"measurements",
"commonly",
"used",
"to",
"characterize",
"postprandial",
"lipemia,",
"but",
"also",
"provide",
"mechanistic",
"insight",
"into",
"the",
"effects",
"of",
"the",
"apo",
"E",
" ",
"gene",
"polymorphism",
"on",
"postprandial",
"lipemia",
"and",
"CAD."
] | [
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
1,
2,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0
] | Apolipoprotein E polymorphism influences postprandial retinyl palmitate but not triglyceride concentrations. To quantify the effect of the apolipoprotein (apo) E polymorphism on the magnitude of postprandial lipemia, we have defined its role in determining the response to a single high-fat meal in a large sample of (N = 474) individuals taking part in the biethnic Atherosclerosis Risk in Communities Study. The profile of postprandial response in plasma was monitored over 8 h by triglyceride, triglyceride-rich lipoprotein (TGRL)-triglyceride , apo B-48/apo B-100 ratio, and retinyl palmitate concentrations, and the apo E polymorphism was determined by DNA amplification and digestion. The frequency of the apo E alleles and their effects on fasting lipid levels in this sample were similar to those reported elsewhere. Postprandial plasma retinyl palmitate response to a high-fat meal with vitamin A was significantly different among apo E genotypes, with delayed clearance in individuals with an epsilon 2 allele, compared with epsilon 3/3 and epsilon 3/4 individuals. In the sample of 397 Caucasians, average retinyl palmitate response was 1,489 micrograms/dl in epsilon 2/3 individuals, compared with 1,037 micrograms/dl in epsilon 3/3 individuals and 1,108 micrograms/dl in epsilon 3/4 individuals. The apo E polymorphism accounted for 7.1% of the interindividual variation in postprandial retinyl palmitate response, a contribution proportionally greater than its well-known effect on fasting LDL-cholesterol. However, despite this effect on postprandial retinyl palmitate, the profile of postprandial triglyceride response was not significantly different among apo E apo E apo E apo E alleles and their effects on fasting lipid levels in this sample were similar to those reported elsewhere. Postprandial plasma retinyl palmitate response to a high-fat meal with vitamin A was significantly different among apo E genotypes, with delayed clearance in individuals with an epsilon 2 allele, compared with epsilon 3/3 and epsilon 3/4 individuals. In the sample of 397 Caucasians, average retinyl palmitate response was 1,489 micrograms/dl in epsilon 2/3 individuals, compared with 1,037 micrograms/dl in epsilon 3/3 individuals and 1,108 micrograms/dl in epsilon 3/4 individuals. The apo E polymorphism accounted for 7.1% of the interindividual variation in postprandial retinyl palmitate response, a contribution proportionally greater than its well-known effect on fasting LDL-cholesterol. However, despite this effect on postprandial retinyl palmitate, the profile of postprandial triglyceride response was not significantly different among apo E genotypes. The profile of postprandial response was consistent between the sample of Caucasians and a smaller sample of black subjects. While these data indicate that the removal of remnant particles from circulation is delayed in subjects with the epsilon 2/3 genotype, there is no reported evidence that the epsilon 2 allele predisposes to coronary artery disease (CAD). The results of this study provide not only a reliable estimate of the magnitude of the effect of the apo E polymorphism on various measurements commonly used to characterize postprandial lipemia, but also provide mechanistic insight into the effects of the apo E gene polymorphism on postprandial lipemia and CAD. | [
2,
18747,
47,
8218,
8061,
19210,
7599,
2199,
22047,
2308,
2084,
13852,
3295,
18,
1942,
8730,
1920,
2495,
1927,
1920,
18747,
12,
11466,
13,
47,
8218,
1990,
1920,
6453,
1927,
19210,
3178,
3847,
16,
2038,
2162,
3608,
2496,
2770,
1922,
7426,
1920,
2644,
1942,
43,
2957,
2149,
17,
3777,
11629,
1922,
43,
3103,
2983,
1927,
12,
56,
33,
28883,
13,
3445,
6303,
3131,
1922,
1920,
2273,
3184,
19730,
9824,
2565,
1922,
7384,
2161,
18,
1920,
5174,
1927,
19210,
2644,
1922,
3582,
1982,
7027,
2338,
28,
50,
2007,
13852,
16,
13852,
17,
5536,
9694,
12,
6030,
1005,
1024,
13,
17,
13852,
16,
11466,
44,
17,
3427,
19,
11466,
44,
17,
2813,
3400,
16,
1930,
7599,
2199,
22047,
3295,
16,
1930,
1920,
11466,
47,
8218,
1982,
3180,
2007,
2678,
6584,
1930,
9379,
18,
1920,
3528,
1927,
1920,
11466,
47,
7096,
1930,
2310,
2564,
1990,
8712,
4486,
2428,
1922,
2052,
2983,
1985,
2551,
1942,
2690,
2568,
10132,
18,
19210,
3582,
7599,
2199,
22047,
2644,
1942,
43,
2149,
17,
3777,
11629,
1956,
6111,
43,
1982,
2567,
2413,
2706,
11466,
47,
7059,
16,
1956,
7083,
7802,
1922,
3445,
1956,
1925,
22206,
22,
5465,
16,
2452,
1956,
22206,
23,
19,
23,
1930,
22206,
23,
19,
24,
3445,
18,
1922,
1920,
2983,
1927,
27671,
21338,
16,
3361,
7599,
2199,
22047,
2644,
1982,
21,
16,
3427,
1026,
13362,
19,
5268,
1922,
22206,
22,
19,
23,
3445,
16,
2452,
1956,
21,
16,
23939,
13362,
19,
5268,
1922,
22206,
23,
19,
23,
3445,
1930,
21,
16,
9123,
13362,
19,
5268,
1922,
22206,
23,
19,
24,
3445,
18,
1920,
11466,
47,
8218,
9448,
1958,
27,
18,
21,
9,
1927,
1920,
2107,
2762,
26487,
4516,
1922,
19210,
7599,
2199,
22047,
2644,
16,
43,
5100,
28267,
3430,
2254,
2496,
2486,
17,
3171,
2495,
1990,
8712,
8017,
17,
5463,
18,
2406,
16,
4281,
2052,
2495,
1990,
19210,
7599,
2199,
22047,
16,
1920,
5174,
1927,
19210,
13852,
2644,
1982,
2084,
2567,
2413,
2706,
11466,
47,
11466,
47,
11466,
47,
11466,
47,
7096,
1930,
2310,
2564,
1990,
8712,
4486,
2428,
1922,
2052,
2983,
1985,
2551,
1942,
2690,
2568,
10132,
18,
19210,
3582,
7599,
2199,
22047,
2644,
1942,
43,
2149,
17,
3777,
11629,
1956,
6111,
43,
1982,
2567,
2413,
2706,
11466,
47,
7059,
16,
1956,
7083,
7802,
1922,
3445,
1956,
1925,
22206,
22,
5465,
16,
2452,
1956,
22206,
23,
19,
23,
1930,
22206,
23,
19,
24,
3445,
18,
1922,
1920,
2983,
1927,
27671,
21338,
16,
3361,
7599,
2199,
22047,
2644,
1982,
21,
16,
3427,
1026,
13362,
19,
5268,
1922,
22206,
22,
19,
23,
3445,
16,
2452,
1956,
21,
16,
23939,
13362,
19,
5268,
1922,
22206,
23,
19,
23,
3445,
1930,
21,
16,
9123,
13362,
19,
5268,
1922,
22206,
23,
19,
24,
3445,
18,
1920,
11466,
47,
8218,
9448,
1958,
27,
18,
21,
9,
1927,
1920,
2107,
2762,
26487,
4516,
1922,
19210,
7599,
2199,
22047,
2644,
16,
43,
5100,
28267,
3430,
2254,
2496,
2486,
17,
3171,
2495,
1990,
8712,
8017,
17,
5463,
18,
2406,
16,
4281,
2052,
2495,
1990,
19210,
7599,
2199,
22047,
16,
1920,
5174,
1927,
19210,
13852,
2644,
1982,
2084,
2567,
2413,
2706,
11466,
47,
7059,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
1,
2,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20052763 | [
"Ex",
"vivo",
"splicing",
"assays",
"of",
"mutations",
"at",
"noncanonical",
"positions",
"of",
"splice",
"sites",
"in",
"USHER",
" ",
"genes.",
"Molecular",
"diagnosis",
"in",
"Usher",
"syndrome",
"type",
"1",
"and",
"2",
"patients",
"led",
"to",
"the",
"identification",
"of",
"21",
"sequence",
"variations",
"located",
"in",
"noncanonical",
"positions",
"of",
"splice",
"sites",
"in",
"MYO7A",
",",
"CDH23",
",",
"USH1C",
",",
"and",
"USH2A",
" ",
"genes.",
"To",
"establish",
"experimentally",
"the",
"splicing",
"pattern",
"of",
"these",
"substitutions,",
"whose",
"impact",
"on",
"splicing",
"is",
"not",
"always",
"predictable",
"by",
"available",
"softwares,",
"ex",
"vivo",
"splicing",
"assays",
"were",
"performed.",
"The",
"branch-point",
"mapping",
"strategy",
"was",
"also",
"used",
"to",
"investigate",
"further",
"a",
"putative",
"branch-point",
"mutation",
"in",
"USH2A",
"intron",
"43.",
"Aberrant",
"splicing",
"was",
"demonstrated",
"for",
"16",
"of",
"the",
"21",
"(76.2%)",
"tested",
"sequence",
"variations.",
"The",
"mutations",
"resulted",
"more",
"frequently",
"in",
"activation",
"of",
"a",
"nearby",
"cryptic",
"splice",
"site",
"or",
"use",
"of",
"a",
"de",
"novo",
"splice",
"site",
"than",
"exon",
"skipping",
"(37.5%).",
"This",
"study",
"allowed",
"the",
"reclassification",
"as",
"splicing",
"mutations",
"of",
"one",
"silent",
"(",
"c.7872G>A",
" ",
"(",
"p.Glu2624Glu",
")",
"in",
"CDH23",
")",
"and",
"four",
"missense",
"mutations",
"(",
"c.2993G>A",
" ",
"(",
"p.Arg998Lys",
")",
"in",
"USH2A",
",",
"c.592G>A",
" ",
"(",
"p.Ala198Thr",
"),",
"c.3503G>C",
"[",
"p.Arg1168Pro",
"c.3503G>C",
" ",
"[p.Arg1168Pro],",
"c.5944G>A",
" ",
"(",
"p.Gly1982Arg",
")",
"in",
"MYO7A",
"),",
"whereas",
"it",
"provided",
"clues",
"about",
"a",
"role",
"in",
"structure/function",
"in",
"four",
"other",
"cases:",
"c.802G>A",
" ",
"(",
"p.Gly268Arg",
"),",
"c.653T>A",
" ",
"(",
"p.Val218Glu",
")",
"(",
"USH2A",
"),",
"and",
"c.397C>T",
" ",
"(",
"p.His133Tyr",
"),",
"c.3502C>T",
" ",
"(",
"p.Arg1168Trp",
")",
"(",
"MYO7A",
").",
"Our",
"data",
"provide",
"insights",
"into",
"the",
"contribution",
"of",
"splicing",
"mutations",
"in",
"Usher",
"genes",
"and",
"illustrate",
"the",
"need",
"to",
"define",
"accurately",
"their",
"splicing",
"outcome",
"for",
"diagnostic",
"purposes."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
1,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
1,
0,
3,
0,
0,
3,
0,
0,
0,
3,
3,
0,
0,
3,
0,
0,
3,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
3,
0,
0,
3,
0,
0,
1,
0,
0,
3,
0,
0,
3,
0,
3,
0,
0,
3,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes. Molecular diagnosis in Usher syndrome type 1 and 2 patients led to the identification of 21 sequence variations located in noncanonical positions of splice sites in MYO7A , CDH23 , USH1C , and USH2A genes. To establish experimentally the splicing pattern of these substitutions, whose impact on splicing is not always predictable by available softwares, ex vivo splicing assays were performed. The branch-point mapping strategy was also used to investigate further a putative branch-point mutation in USH2A intron 43. Aberrant splicing was demonstrated for 16 of the 21 (76.2%) tested sequence variations. The mutations resulted more frequently in activation of a nearby cryptic splice site or use of a de novo splice site than exon skipping (37.5%). This study allowed the reclassification as splicing mutations of one silent ( c.7872G>A ( p.Glu2624Glu ) in CDH23 ) and four missense mutations ( c.2993G>A ( p.Arg998Lys ) in USH2A , c.592G>A ( p.Ala198Thr ), c.3503G>C [ p.Arg1168Pro c.3503G>C [p.Arg1168Pro], c.5944G>A ( p.Gly1982Arg ) in MYO7A ), whereas it provided clues about a role in structure/function in four other cases: c.802G>A ( p.Gly268Arg ), c.653T>A ( p.Val218Glu ) ( USH2A ), and c.397C>T ( p.His133Tyr ), c.3502C>T ( p.Arg1168Trp ) ( MYO7A ). Our data provide insights into the contribution of splicing mutations in Usher genes and illustrate the need to define accurately their splicing outcome for diagnostic purposes. | [
2,
1975,
3597,
8490,
4614,
1927,
3527,
2019,
9341,
9286,
19730,
1923,
6490,
1927,
10708,
3402,
1922,
2022,
2380,
2628,
18,
3272,
3574,
1922,
2022,
2380,
4741,
2601,
21,
1930,
22,
2132,
4866,
1942,
1920,
4824,
1927,
2900,
3244,
6740,
4810,
1922,
9341,
9286,
19730,
1923,
6490,
1927,
10708,
3402,
1922,
15924,
13827,
16,
23927,
4553,
16,
2022,
8600,
1030,
16,
1930,
2022,
6951,
1019,
2628,
18,
1942,
5389,
9568,
1920,
8490,
3114,
1927,
2144,
10682,
16,
6098,
3829,
1990,
8490,
1977,
2084,
6789,
19968,
2007,
3322,
4187,
1036,
16,
1975,
3597,
8490,
4614,
1985,
2593,
18,
1920,
6089,
17,
3575,
7084,
4884,
1982,
2222,
2251,
1942,
4482,
2520,
43,
6770,
6089,
17,
3575,
3979,
1922,
2022,
6951,
1019,
10444,
3941,
18,
9801,
8490,
1982,
3161,
1958,
2641,
1927,
1920,
2900,
12,
5439,
18,
22,
9,
13,
3620,
3244,
6740,
18,
1920,
3527,
4306,
2253,
5467,
1922,
2936,
1927,
43,
15485,
21565,
10708,
3200,
2014,
2485,
1927,
43,
2028,
9441,
10708,
3200,
2254,
7049,
26153,
12,
3191,
18,
25,
9,
13,
18,
2052,
2161,
5563,
1920,
27681,
3123,
1966,
8490,
3527,
1927,
2340,
15381,
12,
45,
18,
5440,
10180,
1029,
34,
43,
12,
58,
18,
9258,
4684,
4561,
4365,
1032,
13,
1922,
23927,
4553,
13,
1930,
3006,
13519,
3527,
12,
45,
18,
22967,
24176,
34,
43,
12,
58,
18,
4582,
26234,
19010,
13,
1922,
2022,
6951,
1019,
16,
45,
18,
4777,
1028,
1029,
34,
43,
12,
58,
18,
10527,
25016,
5856,
13,
16,
45,
18,
11936,
24176,
34,
45,
37,
58,
18,
4582,
12618,
1025,
2216,
45,
18,
11936,
24176,
34,
45,
37,
58,
18,
4582,
12618,
1025,
2216,
39,
16,
45,
18,
21162,
1006,
1029,
34,
43,
12,
58,
18,
3376,
25016,
5896,
1005,
1029,
13,
1922,
15924,
13827,
13,
16,
3417,
2176,
3675,
21511,
3001,
43,
2770,
1922,
3170,
19,
2347,
1922,
3006,
2303,
2919,
30,
45,
18,
3729,
1028,
1029,
34,
43,
12,
58,
18,
3376,
23440,
2419,
13,
16,
45,
18,
4459,
1010,
1031,
34,
43,
12,
58,
18,
2326,
4716,
1025,
4365,
1032,
13,
12,
2022,
6951,
1019,
13,
16,
1930,
45,
18,
27671,
1030,
34,
62,
12,
58,
18,
4167,
13041,
3145,
1005,
13,
16,
45,
18,
11936,
10866,
34,
62,
12,
58,
18,
4582,
12618,
1025,
1997,
1034,
13,
12,
15924,
13827,
13,
18,
2342,
2230,
3394,
8486,
2460,
1920,
5100,
1927,
8490,
3527,
1922,
2022,
2380,
2628,
1930,
11197,
1920,
2942,
1942,
7425,
8941,
2310,
8490,
3924,
1958,
4785,
9323,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
0,
1,
2,
2,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
0,
0,
1,
2,
2,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
1,
2,
2,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
0,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
12145744 | [
"The",
"Xq22",
"inversion",
"breakpoint",
"interrupted",
"a",
"novel",
"Ras-like",
"GTPase",
"gene",
"in",
"a",
"patient",
"with",
"Duchenne",
"muscular",
"dystrophy",
"and",
"profound",
"mental",
"retardation.",
"A",
"male",
"patient",
"with",
"profound",
"mental",
"retardation,",
"athetosis,",
"nystagmus,",
"and",
"severe",
"congenital",
"hypotonia",
"(Duchenne",
"muscular",
"dystrophy",
"[DMD])",
"was",
"previously",
"shown",
"to",
"carry",
"a",
"pericentric",
"inversion",
"of",
"the",
"X",
"chromosome,",
"46,Y,inv(X)(p21.2q22.2).",
"His",
"mother",
"carried",
"this",
"inversion",
"on",
"one",
"X",
"allele.",
"The",
"patient's",
"condition",
"was",
"originally",
"misdiagnosed",
"as",
"cerebral",
"palsy,",
"and",
"only",
"later",
"was",
"it",
"diagnosed",
"as",
"DMD.",
"Because",
"the",
"DMD",
"gene",
"is",
"located",
"at",
"Xp21.2,",
"which",
"is",
"one",
"breakpoint",
"of",
"the",
"inv(X),",
"and",
"because",
"its",
"defects",
"are",
"rarely",
"associated",
"with",
"severe",
"mental",
"retardation,",
"the",
"other",
"clinical",
"features",
"of",
"this",
"patient",
"were",
"deemed",
"likely",
"to",
"be",
"associated",
"with",
"the",
"opposite",
"breakpoint",
"at",
"Xq22.",
"Our",
"precise",
"molecular-cytogenetic",
"characterization",
"of",
"both",
"breakpoints",
"revealed",
"three",
"catastrophic",
"genetic",
"events",
"that",
"had",
"probably",
"influenced",
"neuromuscular",
"and",
"cognitive",
"development:",
"deletion",
"of",
"part",
"of",
"the",
"DMD",
"gene",
"at",
"Xp21.2,",
"duplication",
"of",
"the",
"human",
"proteolipid",
"protein",
" ",
"gene",
"(",
"PLP",
"DMD",
" ",
"gene",
"at",
"Xp21.2,",
"duplication",
"of",
"the",
"human",
"proteolipid",
"protein",
"gene",
"(PLP)",
"at",
"Xq22.2,",
"and",
"disruption",
"of",
"a",
"novel",
"gene.",
"The",
"latter",
"sequence,",
"showing",
"a",
"high",
"degree",
"of",
"homology",
"to",
"the",
"Sec4",
" ",
"gene",
"of",
"yeast,",
"encoded",
"a",
"putative",
"small",
"guanine-protein,",
"Ras",
"-like",
"GTPase",
"that",
"we",
"have",
"termed",
"\"",
"RLGP",
".\"",
"Immunocytochemistry",
"located",
"RLGP",
" ",
"at",
"mitochondria.",
"We",
"speculate",
"that",
"disruption",
"of",
"RLGP",
"DMD",
"Ras",
"-like",
"GTPase",
"gene",
"in",
"a",
"patient",
"with",
"Duchenne",
"muscular",
"dystrophy",
"and",
"profound",
"mental",
"retardation.",
"A",
"male",
"patient",
"with",
"profound",
"mental",
"retardation,",
"athetosis,",
"nystagmus,",
"and",
"severe",
"congenital",
"hypotonia",
"(Duchenne",
"muscular",
"dystrophy",
"[DMD])",
"was",
"previously",
"shown",
"to",
"carry",
"a",
"pericentric",
"inversion",
"of",
"the",
"X",
"chromosome,",
"46,Y,inv(X)(p21.2q22.2).",
"His",
"mother",
"carried",
"this",
"inversion",
"on",
"one",
"X",
"allele.",
"The",
"patient's",
"condition",
"was",
"originally",
"misdiagnosed",
"as",
"cerebral",
"palsy,",
"and",
"only",
"later",
"was",
"it",
"diagnosed",
"as",
"DMD.",
"Because",
"the",
"DMD",
"gene",
"is",
"located",
"at",
"Xp21.2,",
"which",
"is",
"one",
"breakpoint",
"of",
"the",
"inv(X),",
"and",
"because",
"its",
"defects",
"are",
"rarely",
"associated",
"with",
"severe",
"mental",
"retardation,",
"the",
"other",
"clinical",
"features",
"of",
"this",
"patient",
"were",
"deemed",
"likely",
"to",
"be",
"associated",
"with",
"the",
"opposite",
"breakpoint",
"at",
"Xq22.",
"Our",
"precise",
"molecular-cytogenetic",
"characterization",
"of",
"both",
"breakpoints",
"revealed",
"three",
"catastrophic",
"genetic",
"events",
"that",
"had",
"probably",
"influenced",
"neuromuscular",
"and",
"cognitive",
"development:",
"deletion",
"of",
"part",
"of",
"the",
"DMD",
"gene",
"at",
"Xp21.2,",
"duplication",
"of",
"the",
"human",
"proteolipid",
"protein",
"gene",
"(PLP)",
"at",
"Xq22.2,",
"and",
"disruption",
"of",
"a",
"novel",
"gene.",
"The",
"latter",
"sequence,",
"showing",
"a",
"high",
"degree",
"of",
"homology",
"to",
"the",
"Sec4",
"gene",
"of",
"yeast,",
"encoded",
"a",
"putative",
"small",
"guanine-protein,",
"Ras-like",
"GTPase",
"that",
"we",
"have",
"termed",
"\"RLGP.\"",
"Immunocytochemistry",
"located",
"RLGP",
"at",
"mitochondria.",
"We",
"speculate",
"that",
"disruption",
"of",
"RLGP",
"was",
"responsible",
"for",
"the",
"patient's",
"profound",
"mental",
"retardation."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The Xq22 inversion breakpoint interrupted a novel Ras-like GTPase gene in a patient with Duchenne muscular dystrophy and profound mental retardation. A male patient with profound mental retardation, athetosis, nystagmus, and severe congenital hypotonia (Duchenne muscular dystrophy [DMD]) was previously shown to carry a pericentric inversion of the X chromosome, 46,Y,inv(X)(p21.2q22.2). His mother carried this inversion on one X allele. The patient's condition was originally misdiagnosed as cerebral palsy, and only later was it diagnosed as DMD. Because the DMD gene is located at Xp21.2, which is one breakpoint of the inv(X), and because its defects are rarely associated with severe mental retardation, the other clinical features of this patient were deemed likely to be associated with the opposite breakpoint at Xq22. Our precise molecular-cytogenetic characterization of both breakpoints revealed three catastrophic genetic events that had probably influenced neuromuscular and cognitive development: deletion of part of the DMD gene at Xp21.2, duplication of the human proteolipid protein gene ( PLP DMD gene at Xp21.2, duplication of the human proteolipid protein gene (PLP) at Xq22.2, and disruption of a novel gene. The latter sequence, showing a high degree of homology to the Sec4 gene of yeast, encoded a putative small guanine-protein, Ras -like GTPase that we have termed " RLGP ." Immunocytochemistry located RLGP at mitochondria. We speculate that disruption of RLGP DMD Ras -like GTPase gene in a patient with Duchenne muscular dystrophy and profound mental retardation. A male patient with profound mental retardation, athetosis, nystagmus, and severe congenital hypotonia (Duchenne muscular dystrophy [DMD]) was previously shown to carry a pericentric inversion of the X chromosome, 46,Y,inv(X)(p21.2q22.2). His mother carried this inversion on one X allele. The patient's condition was originally misdiagnosed as cerebral palsy, and only later was it diagnosed as DMD. Because the DMD gene is located at Xp21.2, which is one breakpoint of the inv(X), and because its defects are rarely associated with severe mental retardation, the other clinical features of this patient were deemed likely to be associated with the opposite breakpoint at Xq22. Our precise molecular-cytogenetic characterization of both breakpoints revealed three catastrophic genetic events that had probably influenced neuromuscular and cognitive development: deletion of part of the DMD gene at Xp21.2, duplication of the human proteolipid protein gene (PLP) at Xq22.2, and disruption of a novel gene. The latter sequence, showing a high degree of homology to the Sec4 gene of yeast, encoded a putative small guanine-protein, Ras-like GTPase that we have termed "RLGP." Immunocytochemistry located RLGP at mitochondria. We speculate that disruption of RLGP was responsible for the patient's profound mental retardation. | [
2,
1920,
66,
23470,
1028,
14825,
24698,
20291,
43,
4008,
6520,
17,
3189,
14809,
2359,
1922,
43,
2774,
1956,
10677,
22467,
2912,
12330,
19321,
1930,
11098,
5018,
16342,
18,
43,
4005,
2774,
1956,
11098,
5018,
16342,
16,
9468,
19446,
8362,
16,
26133,
11431,
1957,
16,
1930,
4010,
9901,
12201,
6114,
12,
10677,
22467,
2912,
12330,
19321,
37,
20646,
39,
13,
1982,
3024,
2522,
1942,
9875,
43,
10796,
14635,
14825,
1927,
1920,
66,
5597,
16,
4182,
16,
67,
16,
2269,
12,
66,
13,
12,
10313,
18,
22,
23470,
1028,
18,
22,
13,
18,
4167,
7999,
4371,
2052,
14825,
1990,
2340,
66,
5465,
18,
1920,
2774,
11,
61,
2625,
1982,
10398,
23887,
10350,
1966,
6329,
18698,
16,
1930,
2444,
3690,
1982,
2176,
5377,
1966,
20646,
18,
2882,
1920,
20646,
2359,
1977,
4810,
2019,
15930,
4716,
18,
22,
16,
2154,
1977,
2340,
24698,
1927,
1920,
2269,
12,
66,
13,
16,
1930,
2882,
2496,
6007,
2032,
9671,
2458,
1956,
4010,
5018,
16342,
16,
1920,
2303,
2535,
4075,
1927,
2052,
2774,
1985,
14337,
3205,
1942,
1998,
2458,
1956,
1920,
8179,
24698,
2019,
66,
23470,
1028,
18,
2342,
8162,
3272,
17,
18486,
7285,
1927,
2321,
23800,
3404,
2559,
27524,
3299,
3916,
1988,
2430,
6226,
6950,
15829,
1930,
4328,
2740,
30,
5541,
1927,
3131,
1927,
1920,
20646,
2359,
2019,
15930,
4716,
18,
22,
16,
12630,
1927,
1920,
2616,
2174,
16113,
2213,
2359,
12,
21453,
20646,
2359,
2019,
15930,
4716,
18,
22,
16,
12630,
1927,
1920,
2616,
2174,
16113,
2213,
2359,
12,
21453,
13,
2019,
66,
23470,
1028,
18,
22,
16,
1930,
7561,
1927,
43,
4008,
2359,
18,
1920,
6296,
3244,
16,
4570,
43,
2149,
4647,
1927,
9039,
1942,
1920,
2532,
1006,
2359,
1927,
5688,
16,
7905,
43,
6770,
2858,
16904,
17,
2213,
16,
6520,
17,
3189,
14809,
1988,
2038,
2162,
10266,
6,
11929,
19874,
18,
6,
21131,
4810,
11929,
19874,
2019,
6489,
18,
2038,
12322,
1988,
7561,
1927,
11929,
19874,
20646,
6520,
17,
3189,
14809,
2359,
1922,
43,
2774,
1956,
10677,
22467,
2912,
12330,
19321,
1930,
11098,
5018,
16342,
18,
43,
4005,
2774,
1956,
11098,
5018,
16342,
16,
9468,
19446,
8362,
16,
26133,
11431,
1957,
16,
1930,
4010,
9901,
12201,
6114,
12,
10677,
22467,
2912,
12330,
19321,
37,
20646,
39,
13,
1982,
3024,
2522,
1942,
9875,
43,
10796,
14635,
14825,
1927,
1920,
66,
5597,
16,
4182,
16,
67,
16,
2269,
12,
66,
13,
12,
10313,
18,
22,
23470,
1028,
18,
22,
13,
18,
4167,
7999,
4371,
2052,
14825,
1990,
2340,
66,
5465,
18,
1920,
2774,
11,
61,
2625,
1982,
10398,
23887,
10350,
1966,
6329,
18698,
16,
1930,
2444,
3690,
1982,
2176,
5377,
1966,
20646,
18,
2882,
1920,
20646,
2359,
1977,
4810,
2019,
15930,
4716,
18,
22,
16,
2154,
1977,
2340,
24698,
1927,
1920,
2269,
12,
66,
13,
16,
1930,
2882,
2496,
6007,
2032,
9671,
2458,
1956,
4010,
5018,
16342,
16,
1920,
2303,
2535,
4075,
1927,
2052,
2774,
1985,
14337,
3205,
1942,
1998,
2458,
1956,
1920,
8179,
24698,
2019,
66,
23470,
1028,
18,
2342,
8162,
3272,
17,
18486,
7285,
1927,
2321,
23800,
3404,
2559,
27524,
3299,
3916,
1988,
2430,
6226,
6950,
15829,
1930,
4328,
2740,
30,
5541,
1927,
3131,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
14691730 | [
"The",
"PARK8",
" ",
"locus",
"in",
"autosomal",
"dominant",
"parkinsonism:",
"confirmation",
"of",
"linkage",
"and",
"further",
"delineation",
"of",
"the",
"disease-containing",
"interval.",
"Recently,",
"a",
"new",
"locus",
"(",
"PARK8",
")",
"for",
"autosomal",
"dominant",
"parkinsonism",
"has",
"been",
"identified",
"in",
"one",
"large",
"Japanese",
"family.",
"Linkage",
"has",
"been",
"shown",
"to",
"a",
"16-cM",
"centromeric",
"region",
"of",
"chromosome",
"12,",
"between",
"markers",
"D12S1631",
"and",
"D12S339.",
"We",
"tested",
"21",
"white",
"families",
"with",
"Parkinson",
"disease",
"and",
"an",
"inheritance",
"pattern",
"compatible",
"with",
"autosomal",
"dominant",
"transmission",
"for",
"linkage",
"in",
"this",
"region.",
"Criteria",
"for",
"inclusion",
"were",
"at",
"least",
"three",
"affected",
"individuals",
"in",
"more",
"than",
"one",
"generation.",
"A",
"total",
"of",
"29",
"markers",
"were",
"used",
"to",
"saturate",
"the",
"candidate",
"region.",
"One",
"hundred",
"sixty-seven",
"family",
"members",
"were",
"tested",
"(84",
"affected",
"and",
"83",
"unaffected).",
"Under",
"the",
"assumption",
"of",
"heterogeneity",
"and",
"through",
"use",
"of",
"an",
"affecteds-only",
"model,",
"a",
"maximum",
"multipoint",
"LOD",
"score",
"of",
"2.01",
"was",
"achieved",
"in",
"the",
"total",
"sample,",
"with",
"an",
"estimated",
"proportion",
"of",
"families",
"with",
"linkage",
"of",
"0.32.",
"This",
"LOD",
"score",
"is",
"significant",
"for",
"linkage",
"in",
"a",
"replication",
"study",
"and",
"corresponds",
"to",
"a",
"P",
"value",
"of.0047.",
"Two",
"families",
"(family",
"A",
"[German",
"Canadian]",
"and",
"family",
"D",
"[from",
"western",
"Nebraska])",
"reached",
"significant",
"linkage",
"on",
"their",
"own,",
"with",
"a",
"combined",
"maximum",
"multipoint",
"LOD",
"score",
"of",
"3.33,",
"calculated",
"with",
"an",
"affecteds-only",
"model",
"(family",
"A:",
"LOD",
"score",
"1.67,",
"P=.0028;",
"family",
"D:",
"LOD",
"score",
"1.67,",
"P=.0028).",
"When",
"a",
"penetrance-dependent",
"model",
"was",
"calculated,",
"the",
"combined",
"multipoint",
"LOD",
"score",
"achieved",
"was",
"3.92",
"(family",
"A:",
"LOD",
"score",
"1.68,",
"P=.0027;",
"family",
"D:",
"LOD",
"score",
"2.24,",
"P=.0007).",
"On",
"the",
"basis",
"of",
"the",
"multipoint",
"analysis",
"for",
"the",
"combined",
"families",
"A",
"and",
"D,",
"the",
"1-LOD",
"support",
"interval",
"suggests",
"that",
"the",
"most",
"likely",
"disease",
"location",
"is",
"between",
"a",
"CA",
"repeat",
"polymorphism",
"on",
"genomic",
"clone",
"AC025253",
"(44.5",
"Mb)",
"and",
"marker",
"D12S1701",
"(47.7",
"Mb).",
"Our",
"data",
"provide",
"evidence",
"that",
"the",
"PARK8",
" ",
"locus",
"is",
"responsible",
"for",
"the",
"disease",
"in",
"a",
"subset",
"of",
"families",
"of",
"white",
"ancestry",
"with",
"autosomal",
"dominant",
"parkinsonism,",
"suggesting",
"that",
"it",
"could",
"be",
"a",
"more",
"common",
"locus."
] | [
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval. Recently, a new locus ( PARK8 ) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus. | [
2,
1920,
7607,
1025,
6730,
1922,
13027,
6379,
26214,
30,
12398,
1927,
8611,
1930,
2520,
24852,
1927,
1920,
2573,
17,
3165,
4979,
18,
3998,
16,
43,
2814,
6730,
12,
7607,
1025,
13,
1958,
13027,
6379,
26214,
2258,
2252,
2899,
1922,
2340,
3103,
10405,
3416,
18,
8611,
2258,
2252,
2522,
1942,
43,
2641,
17,
3195,
25790,
3031,
1927,
5597,
2369,
16,
2192,
4432,
8524,
24900,
25159,
1009,
1930,
8524,
24900,
6498,
1026,
18,
2038,
3620,
2900,
4511,
5767,
1956,
10124,
2573,
1930,
1925,
15762,
3114,
11290,
1956,
13027,
6379,
5303,
1958,
8611,
1922,
2052,
3031,
18,
4164,
1958,
6125,
1985,
2019,
3464,
2559,
4218,
3445,
1922,
2253,
2254,
2340,
4841,
18,
43,
2698,
1927,
3230,
4432,
1985,
2251,
1942,
20924,
2010,
1920,
6610,
3031,
18,
2340,
8295,
14063,
17,
5260,
3416,
4678,
1985,
3620,
12,
5686,
4218,
1930,
5893,
10403,
13,
18,
2441,
1920,
7235,
1927,
6808,
1930,
2596,
2485,
1927,
1925,
4218,
1036,
17,
2444,
2322,
16,
43,
4419,
20677,
4418,
15187,
3593,
1927,
22,
18,
3287,
1982,
5032,
1922,
1920,
2698,
2983,
16,
1956,
1925,
4185,
4242,
1927,
5767,
1956,
8611,
1927,
20,
18,
3323,
18,
2052,
15187,
3593,
1977,
2228,
1958,
8611,
1922,
43,
5158,
2161,
1930,
8852,
1942,
43,
58,
3113,
1927,
18,
11373,
1027,
18,
2288,
5767,
12,
3416,
43,
37,
12194,
13870,
39,
1930,
3416,
46,
37,
2037,
4540,
15749,
29375,
7640,
39,
13,
6690,
2228,
8611,
1990,
2310,
6614,
16,
1956,
43,
4252,
4419,
20677,
4418,
15187,
3593,
1927,
23,
18,
3401,
16,
3561,
1956,
1925,
4218,
1036,
17,
2444,
2322,
12,
3416,
43,
30,
15187,
3593,
21,
18,
4838,
16,
58,
33,
18,
9299,
1025,
31,
3416,
46,
30,
15187,
3593,
21,
18,
4838,
16,
58,
33,
18,
9299,
1025,
13,
18,
2469,
43,
22035,
17,
3100,
2322,
1982,
3561,
16,
1920,
4252,
20677,
4418,
15187,
3593,
5032,
1982,
23,
18,
6224,
12,
3416,
43,
30,
15187,
3593,
21,
18,
5117,
16,
58,
33,
18,
9299,
1027,
31,
3416,
46,
30,
15187,
3593,
22,
18,
2686,
16,
58,
33,
18,
3240,
1027,
13,
18,
1990,
1920,
4859,
1927,
1920,
20677,
4418,
2333,
1958,
1920,
4252,
5767,
43,
1930,
46,
16,
1920,
21,
17,
15187,
3373,
4979,
4015,
1988,
1920,
2501,
3205,
2573,
5185,
1977,
2192,
43,
2332,
6865,
8218,
1990,
4935,
7842,
2000,
11636,
8982,
3786,
12,
4044,
18,
25,
5667,
13,
1930,
4966,
8524,
24900,
17720,
1009,
12,
4261,
18,
27,
5667,
13,
18,
2342,
2230,
3394,
3095,
1988,
1920,
7607,
1025,
6730,
1977,
5061,
1958,
1920,
2573,
1922,
43,
6728,
1927,
5767,
1927,
4511,
15419,
1956,
13027,
6379,
26214,
16,
3783,
1988,
2176,
2578,
1998,
43,
2253,
3059,
6730,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9042906 | [
"Congenital",
"anomalies",
"and",
"childhood",
"cancer",
"in",
"Great",
"Britain.",
"The",
"presence",
"of",
"cancer",
"and",
"a",
"congenital",
"anomaly",
"in",
"the",
"same",
"child",
"may",
"be",
"explained",
"in",
"certain",
"cases",
"by",
"an",
"underlying",
"genetic",
"abnormality.",
"The",
"study",
"of",
"these",
"associations",
"may",
"lead",
"to",
"the",
"identification",
"of",
"genes",
"that",
"are",
"important",
"in",
"both",
"processes.",
"We",
"have",
"examined",
"the",
"records",
"of",
"20,304",
"children",
"with",
"cancer",
"in",
"Britain,",
"who",
"were",
"entered",
"into",
"the",
"National",
"Registry",
"of",
"Childhood",
"Tumors",
"(NRCT)",
"during",
"1971-86,",
"for",
"the",
"presence",
"of",
"congenital",
"anomalies.",
"The",
"frequency",
"of",
"anomalies",
"was",
"much",
"higher",
"among",
"children",
"with",
"solid",
"tumors",
"(4.4%)",
"than",
"among",
"those",
"with",
"leukemia",
"or",
"lymphoma",
"(2.6%;",
"P",
"<",
".0001).",
"The",
"types",
"of",
"cancer",
"with",
"the",
"highest",
"rates",
"of",
"anomalies",
"were",
"Wilms",
"tumor",
"(8.1%),",
"Ewing",
"sarcoma",
"(5.8%),",
"hepatoblastoma",
"(6.4%),",
"and",
"gonadal",
"and",
"germ-cell",
"tumors",
"(6.4%).",
"Cases",
"of",
"spina",
"bifida",
"and",
"abnormalities",
"of",
"the",
"eye,",
"ribs,",
"and",
"spine",
"were",
"more",
"common",
"in",
"children",
"with",
"cancer",
"than",
"among",
"population-based",
"controls.",
"Future",
"studies",
"may",
"be",
"directed",
"toward",
"identifying",
"the",
"developmental",
"pathways",
"and",
"the",
"relevant",
"genes",
"that",
"are",
"involved",
"in",
"the",
"overlap",
"between",
"pediatric",
"cancer",
"and",
"malformation."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Congenital anomalies and childhood cancer in Great Britain. The presence of cancer and a congenital anomaly in the same child may be explained in certain cases by an underlying genetic abnormality. The study of these associations may lead to the identification of genes that are important in both processes. We have examined the records of 20,304 children with cancer in Britain, who were entered into the National Registry of Childhood Tumors (NRCT) during 1971-86, for the presence of congenital anomalies. The frequency of anomalies was much higher among children with solid tumors (4.4%) than among those with leukemia or lymphoma (2.6%; P < .0001). The types of cancer with the highest rates of anomalies were Wilms tumor (8.1%), Ewing sarcoma (5.8%), hepatoblastoma (6.4%), and gonadal and germ-cell tumors (6.4%). Cases of spina bifida and abnormalities of the eye, ribs, and spine were more common in children with cancer than among population-based controls. Future studies may be directed toward identifying the developmental pathways and the relevant genes that are involved in the overlap between pediatric cancer and malformation. | [
2,
9901,
13621,
1930,
7238,
2539,
1922,
4733,
22197,
2005,
18,
1920,
2990,
1927,
2539,
1930,
43,
9901,
20950,
1922,
1920,
2841,
2748,
2278,
1998,
6094,
1922,
4908,
2919,
2007,
1925,
5030,
3299,
14311,
18,
1920,
2161,
1927,
2144,
5253,
2278,
2949,
1942,
1920,
4824,
1927,
2628,
1988,
2032,
2715,
1922,
2321,
4028,
18,
2038,
2162,
3572,
1920,
7123,
1927,
2036,
16,
23490,
3069,
1956,
2539,
1922,
22197,
2005,
16,
2746,
1985,
10725,
2460,
1920,
3852,
10557,
1927,
7238,
3861,
12,
5214,
2341,
13,
2409,
21307,
17,
5713,
16,
1958,
1920,
2990,
1927,
9901,
13621,
18,
1920,
3528,
1927,
13621,
1982,
4186,
2580,
2706,
3069,
1956,
5358,
3861,
12,
24,
18,
24,
9,
13,
2254,
2706,
2690,
1956,
8111,
2014,
8636,
12,
22,
18,
26,
9,
31,
58,
32,
18,
6060,
13,
18,
1920,
3584,
1927,
2539,
1956,
1920,
4554,
3389,
1927,
13621,
1985,
8534,
2800,
2798,
12,
28,
18,
21,
9,
13,
16,
29460,
13970,
12,
25,
18,
28,
9,
13,
16,
5746,
10998,
12,
26,
18,
24,
9,
13,
16,
1930,
21282,
1930,
4363,
17,
2024,
3861,
12,
26,
18,
24,
9,
13,
18,
2919,
1927,
7707,
1019,
21724,
1019,
1930,
6754,
1927,
1920,
5723,
16,
5216,
1036,
16,
1930,
8859,
1985,
2253,
3059,
1922,
3069,
1956,
2539,
2254,
2706,
2973,
17,
2454,
3562,
18,
4115,
2351,
2278,
1998,
6554,
4205,
6993,
1920,
5878,
3873,
1930,
1920,
4494,
2628,
1988,
2032,
3286,
1922,
1920,
7713,
2192,
7460,
2539,
1930,
22138,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8651311 | [
"Conclusion",
"of",
"LOD-score",
"analysis",
"for",
"family",
"data",
"generated",
"under",
"two-locus",
"models.",
"The",
"power",
"to",
"detect",
"linkage",
"by",
"the",
"LOD-score",
"method",
"is",
"investigated",
"here",
"for",
"diseases",
"that",
"depend",
"on",
"the",
"effects",
"of",
"two",
"genes.",
"The",
"classical",
"strategy",
"is,",
"first,",
"to",
"detect",
"a",
"major-gene",
"(MG)",
"effect",
"by",
"segregation",
"analysis",
"and,",
"second,",
"to",
"seek",
"for",
"linkage",
"with",
"genetic",
"markers",
"by",
"the",
"LOD-score",
"method",
"using",
"the",
"MG",
"parameters.",
"We",
"already",
"showed",
"that",
"segregation",
"analysis",
"can",
"lead",
"to",
"evidence",
"for",
"a",
"MG",
"effect",
"for",
"many",
"two-locus",
"models,",
"with",
"the",
"estimates",
"of",
"the",
"MG",
"parameters",
"being",
"very",
"different",
"from",
"those",
"of",
"the",
"two",
"genes",
"involved",
"in",
"the",
"disease.",
"We",
"show",
"here",
"that",
"use",
"of",
"these",
"MG",
"parameter",
"estimates",
"in",
"the",
"LOD-score",
"analysis",
"may",
"lead",
"to",
"a",
"failure",
"to",
"detect",
"linkage",
"for",
"some",
"two-locus",
"models.",
"For",
"these",
"models,",
"use",
"of",
"the",
"sib-pair",
"method",
"gives",
"a",
"non-negligible",
"increase",
"of",
"power",
"to",
"detect",
"linkage.",
"The",
"linkage-homogeneity",
"test",
"among",
"subsamples",
"differing",
"for",
"the",
"familial",
"disease",
"distribution",
"provides",
"evidence",
"of",
"parameter",
"misspecification,",
"when",
"the",
"MG",
"parameters",
"are",
"used.",
"Moreover,",
"for",
"most",
"of",
"the",
"models,",
"use",
"of",
"the",
"MG",
"parameters",
"in",
"LOD-score",
"analysis",
"leads",
"to",
"a",
"large",
"bias",
"in",
"estimation",
"of",
"the",
"recombination",
"fraction",
"and",
"sometimes",
"also",
"to",
"a",
"rejection",
"of",
"linkage",
"for",
"the",
"true",
"recombination",
"fraction.",
"A",
"final",
"important",
"point",
"is",
"that",
"a",
"strong",
"evidence",
"of",
"an",
"MG",
"effect,",
"obtained",
"by",
"segregation",
"analysis,",
"does",
"not",
"necessarily",
"imply",
"that",
"linkage",
"will",
"be",
"detected",
"for",
"at",
"least",
"one",
"of",
"the",
"two",
"genes,",
"even",
"with",
"the",
"true",
"parameters",
"and",
"with",
"a",
"close",
"informative",
"marker."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Conclusion of LOD-score analysis for family data generated under two-locus models. The power to detect linkage by the LOD-score method is investigated here for diseases that depend on the effects of two genes. The classical strategy is, first, to detect a major-gene (MG) effect by segregation analysis and, second, to seek for linkage with genetic markers by the LOD-score method using the MG parameters. We already showed that segregation analysis can lead to evidence for a MG effect for many two-locus models, with the estimates of the MG parameters being very different from those of the two genes involved in the disease. We show here that use of these MG parameter estimates in the LOD-score analysis may lead to a failure to detect linkage for some two-locus models. For these models, use of the sib-pair method gives a non-negligible increase of power to detect linkage. The linkage-homogeneity test among subsamples differing for the familial disease distribution provides evidence of parameter misspecification, when the MG parameters are used. Moreover, for most of the models, use of the MG parameters in LOD-score analysis leads to a large bias in estimation of the recombination fraction and sometimes also to a rejection of linkage for the true recombination fraction. A final important point is that a strong evidence of an MG effect, obtained by segregation analysis, does not necessarily imply that linkage will be detected for at least one of the two genes, even with the true parameters and with a close informative marker. | [
2,
4180,
1927,
15187,
17,
3593,
2333,
1958,
3416,
2230,
3999,
2441,
2288,
17,
6730,
3130,
18,
1920,
4215,
1942,
4277,
8611,
2007,
1920,
15187,
17,
3593,
2417,
1977,
3845,
3410,
1958,
3902,
1988,
4224,
1990,
1920,
2564,
1927,
2288,
2628,
18,
1920,
8445,
4884,
1977,
16,
2561,
16,
1942,
4277,
43,
3044,
17,
2359,
12,
2786,
13,
2495,
2007,
12707,
2333,
1930,
16,
2812,
16,
1942,
7592,
1958,
8611,
1956,
3299,
4432,
2007,
1920,
15187,
17,
3593,
2417,
2193,
1920,
2786,
3673,
18,
2038,
6064,
2594,
1988,
12707,
2333,
2112,
2949,
1942,
3095,
1958,
43,
2786,
2495,
1958,
3086,
2288,
17,
6730,
3130,
16,
1956,
1920,
5280,
1927,
1920,
2786,
3673,
3301,
3345,
2413,
2037,
2690,
1927,
1920,
2288,
2628,
3286,
1922,
1920,
2573,
18,
2038,
2146,
3410,
1988,
2485,
1927,
2144,
2786,
5817,
5280,
1922,
1920,
15187,
17,
3593,
2333,
2278,
2949,
1942,
43,
4574,
1942,
4277,
8611,
1958,
2673,
2288,
17,
6730,
3130,
18,
1958,
2144,
3130,
16,
2485,
1927,
1920,
9643,
17,
3715,
2417,
10006,
43,
2447,
17,
12613,
2760,
1927,
4215,
1942,
4277,
8611,
18,
1920,
8611,
17,
15532,
2648,
2706,
25705,
1036,
12873,
1958,
1920,
11444,
2573,
3282,
4558,
3095,
1927,
5817,
5276,
10231,
1943,
16,
2469,
1920,
2786,
3673,
2032,
2251,
18,
3950,
16,
1958,
2501,
1927,
1920,
3130,
16,
2485,
1927,
1920,
2786,
3673,
1922,
15187,
17,
3593,
2333,
5029,
1942,
43,
3103,
5353,
1922,
7557,
1927,
1920,
7827,
3906,
1930,
8929,
2222,
1942,
43,
10820,
1927,
8611,
1958,
1920,
6228,
7827,
3906,
18,
43,
3948,
2715,
3575,
1977,
1988,
43,
3206,
3095,
1927,
1925,
2786,
2495,
16,
2926,
2007,
12707,
2333,
16,
3731,
2084,
9409,
12477,
1988,
8611,
2832,
1998,
3330,
1958,
2019,
3464,
2340,
1927,
1920,
2288,
2628,
16,
3385,
1956,
1920,
6228,
3673,
1930,
1956,
43,
5428,
12840,
4966,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
23122587 | [
"Mutations",
"of",
"the",
"gene",
"encoding",
"otogelin",
" ",
"are",
"a",
"cause",
"of",
"autosomal-recessive",
"nonsyndromic",
"moderate",
"hearing",
"impairment.",
"Already",
"40",
"genes",
"have",
"been",
"identified",
"for",
"autosomal-recessive",
"nonsyndromic",
"hearing",
"impairment",
"(arNSHI);",
"however,",
"many",
"more",
"genes",
"are",
"still",
"to",
"be",
"identified.",
"In",
"a",
"Dutch",
"family",
"segregating",
"arNSHI,",
"homozygosity",
"mapping",
"revealed",
"a",
"2.4",
"Mb",
"homozygous",
"region",
"on",
"chromosome",
"11",
"in",
"p15.1-15.2,",
"which",
"partially",
"overlapped",
"with",
"the",
"previously",
"described",
"DFNB18",
" ",
"locus.",
"However,",
"no",
"putative",
"pathogenic",
"variants",
"were",
"found",
"in",
"USH1C",
",",
"the",
"gene",
"mutated",
"in",
"DFNB18",
"hearing",
"impairment.",
"The",
"homozygous",
"region",
"contained",
"12",
"additional",
"annotated",
"genes",
"including",
"OTOG",
",",
"the",
"gene",
"encoding",
"otogelin",
",",
"a",
"component",
"of",
"the",
"tectorial",
"membrane.",
"It",
"is",
"thought",
"that",
"otogelin",
"contributes",
"to",
"the",
"stability",
"and",
"strength",
"of",
"this",
"membrane",
"through",
"interaction",
"or",
"stabilization",
"of",
"its",
"constituent",
"fibers.",
"The",
"murine",
" ",
"orthologous",
"gene",
"was",
"already",
"known",
"to",
"cause",
"hearing",
"loss",
"when",
"defective.",
"Analysis",
"of",
"OTOG",
" ",
"in",
"the",
"Dutch",
"family",
"revealed",
"a",
"homozygous",
"1",
" ",
"bp",
"deletion,",
"c.5508delC",
",",
"which",
"leads",
"to",
"a",
"shift",
"in",
"the",
"reading",
"frame",
"and",
"a",
"premature",
"stop",
"codon,",
"p.Ala1838ProfsX31",
".",
"Further",
"screening",
" ",
"of",
"60",
"unrelated",
"probands",
"from",
"Spanish",
"arNSHI",
"families",
"detected",
"compound",
"heterozygous",
"OTOG",
" ",
"mutations",
"in",
"one",
"family,",
"c.6347C>T",
" ",
"(",
"p.Pro2116Leu",
")",
"and",
"c.",
"6559C>T",
" ",
"(",
"p.Arg2187X",
").",
"The",
"missense",
"mutation",
"p.Pro2116Leu",
" ",
"affects",
"a",
"highly",
"conserved",
"residue",
"in",
"the",
"fourth",
"von",
"Willebrand",
"factor",
"type",
"D",
"domain",
"of",
"otogelin.",
"The",
"subjects",
"with",
"OTOG",
" ",
"mutations",
"have",
"a",
"moderate",
"hearing",
"impairment,",
"which",
"can",
"be",
"associated",
"with",
"vestibular",
"dysfunction.",
"The",
"flat",
"to",
"shallow",
"\"U\"",
"or",
"slightly",
"downsloping",
"shaped",
"audiograms",
"closely",
"resembled",
"audiograms",
"of",
"individuals",
"with",
"recessive",
"mutations",
"in",
"the",
"gene",
"encoding",
"α-tectorin",
",",
"another",
"component",
"of",
"the",
"tectorial",
"membrane.",
"This",
"distinctive",
"phenotype",
"may",
"represent",
"a",
"clue",
"to",
"orientate",
"the",
"molecular",
"diagnosis."
] | [
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C , the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG , the gene encoding otogelin , a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC , which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31 . Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T ( p.Pro2116Leu ) and c. 6559C>T ( p.Arg2187X ). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin , another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis. | [
2,
3527,
1927,
1920,
2359,
5797,
7608,
25354,
1921,
2032,
43,
3936,
1927,
13027,
17,
13992,
23428,
3883,
3264,
5086,
8512,
6159,
18,
6064,
3040,
2628,
2162,
2252,
2899,
1958,
13027,
17,
13992,
23428,
3883,
3264,
8512,
6159,
12,
26506,
6150,
1033,
13,
31,
2406,
16,
3086,
2253,
2628,
2032,
3974,
1942,
1998,
2899,
18,
1922,
43,
15150,
3416,
29185,
26506,
6150,
1033,
16,
29992,
7084,
3404,
43,
22,
18,
24,
5667,
9419,
3031,
1990,
5597,
2513,
1922,
26579,
18,
21,
17,
2461,
18,
22,
16,
2154,
6426,
17389,
1956,
1920,
3024,
2910,
8122,
17046,
3928,
6730,
18,
2406,
16,
2239,
6770,
8070,
4936,
1985,
2435,
1922,
2022,
8600,
1030,
16,
1920,
2359,
8336,
1922,
8122,
17046,
3928,
8512,
6159,
18,
1920,
9419,
3031,
5543,
2369,
3281,
10633,
2628,
2710,
7608,
2021,
16,
1920,
2359,
5797,
7608,
25354,
1921,
16,
43,
4594,
1927,
1920,
18671,
2684,
2086,
3260,
18,
2176,
1977,
6212,
1988,
7608,
25354,
1921,
7624,
1942,
1920,
5057,
1930,
4568,
1927,
2052,
3260,
2596,
2835,
2014,
10281,
1927,
2496,
18690,
6989,
18,
1920,
7135,
18907,
2359,
1982,
6064,
3171,
1942,
3936,
8512,
3257,
2469,
9785,
18,
2333,
1927,
7608,
2021,
1922,
1920,
15150,
3416,
3404,
43,
9419,
21,
4149,
5541,
16,
45,
18,
16685,
1025,
16878,
1030,
16,
2154,
5029,
1942,
43,
5950,
1922,
1920,
7461,
7673,
1930,
43,
9839,
6875,
8905,
16,
58,
18,
10527,
25973,
1025,
2216,
3544,
12001,
1009,
18,
2520,
4449,
1927,
3276,
10295,
23259,
2037,
13289,
26506,
6150,
1033,
5767,
3330,
3547,
9589,
7608,
2021,
3527,
1922,
2340,
3416,
16,
45,
18,
4968,
6106,
1030,
34,
62,
12,
58,
18,
1965,
4716,
3672,
1952,
1032,
13,
1930,
45,
18,
4459,
7308,
1030,
34,
62,
12,
58,
18,
4582,
4716,
8851,
1039,
13,
18,
1920,
13519,
3979,
58,
18,
1965,
4716,
3672,
1952,
1032,
6886,
43,
3626,
5305,
6181,
1922,
1920,
8776,
14147,
30067,
2991,
2601,
46,
3418,
1927,
7608,
25354,
1921,
18,
1920,
3297,
1956,
7608,
2021,
3527,
2162,
43,
5086,
8512,
6159,
16,
2154,
2112,
1998,
2458,
1956,
15752,
5273,
18,
1920,
9778,
1942,
17272,
6,
63,
6,
2014,
5733,
26355,
6012,
9219,
9132,
18609,
28218,
6538,
22795,
18609,
28218,
1927,
3445,
1956,
13992,
3527,
1922,
1920,
2359,
5797,
160,
17,
18671,
2684,
1921,
16,
3741,
4594,
1927,
1920,
18671,
2684,
2086,
3260,
18,
2052,
15308,
4629,
2278,
3015,
43,
2111,
2182,
1942,
5567,
2010,
1920,
3272,
3574,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8651318 | [
"Detection",
"of",
"linkage",
"to",
"affective",
"disorders",
"in",
"the",
"catalogued",
"Amish",
"pedigrees:",
"a",
"reply",
"to",
"Pauls",
"et",
"al."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Detection of linkage to affective disorders in the catalogued Amish pedigrees: a reply to Pauls et al. | [
2,
3805,
1927,
8611,
1942,
11863,
4414,
1922,
1920,
29743,
1007,
15665,
6150,
22336,
1036,
30,
43,
4856,
1012,
1942,
15275,
1036,
2140,
1969,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
1729895 | [
"Decreased",
"fecundability",
"in",
"Hutterite",
"couples",
"sharing",
"HLA-DR",
".",
"To",
"study",
"the",
"effects",
"of",
"parental",
"HLA",
" ",
"sharing",
"on",
"pregnancy",
"outcome,",
"we",
"initiated",
"population-based",
"studies",
"in",
"the",
"Hutterites.",
"We",
"previously",
"reported",
"longer",
"intervals",
"from",
"marriage",
"to",
"each",
"birth",
"among",
"couples",
"sharing",
"HLA",
",",
"particularly",
"HLA-DR",
".",
"In",
"the",
"present",
"report,",
"we",
"present",
"the",
"results",
"of",
"a",
"prospective,",
"5-year",
"study",
"of",
"fecundability",
"and",
"fetal",
"loss",
"rates",
"in",
"this",
"population.",
"Between",
"April",
"1986",
"and",
"April",
"1991,",
"154",
"pregnancies",
"were",
"observed",
"in",
"104",
"couples.",
"The",
"median",
"number",
"of",
"months",
"of",
"unprotected",
"intercourse",
"to",
"a",
"positive",
"pregnancy",
"test",
"was",
"significantly",
"longer",
"among",
"couples",
"sharing",
"HLA-DR",
"who",
"stopped",
"nursing",
"prior",
"to",
"the",
"first",
"menses",
"as",
"compared",
"with",
"couples",
"not",
"sharing",
"HLA-DR",
"who",
"stopped",
"nursing",
"prior",
"to",
"the",
"first",
"menses",
"(5.1",
"vs.",
"2.0",
"mo,",
"respectively;",
"P",
"=",
".016).",
"Fetal",
"loss",
"rates",
"were",
"increased",
"among",
"couples",
"sharing",
"HLA-B",
"HLA-DR",
"HLA-DR",
" ",
"who",
"stopped",
"nursing",
"prior",
"to",
"the",
"first",
"menses",
"as",
"compared",
"with",
"couples",
"not",
"sharing",
"HLA-DR",
"who",
"stopped",
"nursing",
"prior",
"to",
"the",
"first",
"menses",
"(5.1",
"vs.",
"2.0",
"mo,",
"respectively;",
"P",
"=",
".016).",
"Fetal",
"loss",
"rates",
"were",
"increased",
"among",
"couples",
"sharing",
"HLA-B",
"as",
"compared",
"with",
"couples",
"not",
"sharing",
"HLA-B",
"(.23",
"vs.",
".12,",
"respectively;",
"P",
"=",
".041,",
"adjusted",
"for",
"age,",
"gravidity,",
"and",
"kinship).",
"These",
"data",
"suggest",
"that",
"our",
"earlier",
"observations",
"of",
"increased",
"birth",
"interval",
"lengths",
"among",
"Hutterite",
"couples",
"sharing",
"HLA",
"were",
"predominantly",
"due",
"to",
"longer",
"intervals",
"until",
"a",
"clinical",
"pregnancy",
"among",
"couples",
"sharing",
"HLA-DR",
" ",
"and,",
"to",
"a",
"lesser",
"degree,",
"were",
"due",
"to",
"increased",
"fetal",
"loss",
"rates",
"among",
"couples",
"sharing",
"HLA-B",
"HLA",
"HLA-B",
" ",
"(.23",
"vs.",
".12,",
"respectively;",
"P",
"=",
".041,",
"adjusted",
"for",
"age,",
"gravidity,",
"and",
"kinship).",
"These",
"data",
"suggest",
"that",
"our",
"earlier",
"observations",
"of",
"increased",
"birth",
"interval",
"lengths",
"among",
"Hutterite",
"couples",
"sharing",
"HLA",
"were",
"predominantly",
"due",
"to",
"longer",
"intervals",
"until",
"a",
"clinical",
"pregnancy",
"among",
"couples",
"sharing",
"HLA-DR",
"and,",
"to",
"a",
"lesser",
"degree,",
"were",
"due",
"to",
"increased",
"fetal",
"loss",
"rates",
"among",
"couples",
"sharing",
"HLA-B."
] | [
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Decreased fecundability in Hutterite couples sharing HLA-DR . To study the effects of parental HLA sharing on pregnancy outcome, we initiated population-based studies in the Hutterites. We previously reported longer intervals from marriage to each birth among couples sharing HLA , particularly HLA-DR . In the present report, we present the results of a prospective, 5-year study of fecundability and fetal loss rates in this population. Between April 1986 and April 1991, 154 pregnancies were observed in 104 couples. The median number of months of unprotected intercourse to a positive pregnancy test was significantly longer among couples sharing HLA-DR who stopped nursing prior to the first menses as compared with couples not sharing HLA-DR who stopped nursing prior to the first menses (5.1 vs. 2.0 mo, respectively; P = .016). Fetal loss rates were increased among couples sharing HLA-B HLA-DR HLA-DR who stopped nursing prior to the first menses as compared with couples not sharing HLA-DR who stopped nursing prior to the first menses (5.1 vs. 2.0 mo, respectively; P = .016). Fetal loss rates were increased among couples sharing HLA-B as compared with couples not sharing HLA-B (.23 vs. .12, respectively; P = .041, adjusted for age, gravidity, and kinship). These data suggest that our earlier observations of increased birth interval lengths among Hutterite couples sharing HLA were predominantly due to longer intervals until a clinical pregnancy among couples sharing HLA-DR and, to a lesser degree, were due to increased fetal loss rates among couples sharing HLA-B HLA HLA-B (.23 vs. .12, respectively; P = .041, adjusted for age, gravidity, and kinship). These data suggest that our earlier observations of increased birth interval lengths among Hutterite couples sharing HLA were predominantly due to longer intervals until a clinical pregnancy among couples sharing HLA-DR and, to a lesser degree, were due to increased fetal loss rates among couples sharing HLA-B. | [
2,
3261,
24501,
2550,
1922,
21033,
1967,
2394,
14002,
10763,
7225,
17,
2324,
18,
1942,
2161,
1920,
2564,
1927,
7213,
7225,
10763,
1990,
5284,
3924,
16,
2038,
7796,
2973,
17,
2454,
2351,
1922,
1920,
21033,
1967,
2923,
18,
2038,
3024,
2568,
4872,
6087,
2037,
17960,
1942,
2362,
5043,
2706,
14002,
10763,
7225,
16,
4443,
7225,
17,
2324,
18,
1922,
1920,
2481,
3809,
16,
2038,
2481,
1920,
2274,
1927,
43,
6315,
16,
25,
17,
2476,
2161,
1927,
24501,
2550,
1930,
5944,
3257,
3389,
1922,
2052,
2973,
18,
2192,
11071,
11367,
1930,
11071,
8802,
16,
14396,
12675,
1985,
2528,
1922,
8824,
14002,
18,
1920,
4181,
2529,
1927,
3221,
1927,
24362,
20689,
1942,
43,
2843,
5284,
2648,
1982,
2567,
4872,
2706,
14002,
10763,
7225,
17,
2324,
2746,
12032,
8448,
3432,
1942,
1920,
2561,
13336,
1918,
1966,
2452,
1956,
14002,
2084,
10763,
7225,
17,
2324,
2746,
12032,
8448,
3432,
1942,
1920,
2561,
13336,
1918,
12,
25,
18,
21,
3201,
18,
22,
18,
20,
2661,
16,
2763,
31,
58,
33,
18,
17300,
13,
18,
5944,
3257,
3389,
1985,
2502,
2706,
14002,
10763,
7225,
17,
44,
7225,
17,
2324,
7225,
17,
2324,
2746,
12032,
8448,
3432,
1942,
1920,
2561,
13336,
1918,
1966,
2452,
1956,
14002,
2084,
10763,
7225,
17,
2324,
2746,
12032,
8448,
3432,
1942,
1920,
2561,
13336,
1918,
12,
25,
18,
21,
3201,
18,
22,
18,
20,
2661,
16,
2763,
31,
58,
33,
18,
17300,
13,
18,
5944,
3257,
3389,
1985,
2502,
2706,
14002,
10763,
7225,
17,
44,
1966,
2452,
1956,
14002,
2084,
10763,
7225,
17,
44,
12,
18,
3020,
3201,
18,
18,
2369,
16,
2763,
31,
58,
33,
18,
26114,
16,
4967,
1958,
2632,
16,
12413,
5212,
16,
1930,
30082,
3050,
13,
18,
2144,
2230,
3220,
1988,
2342,
5556,
5184,
1927,
2502,
5043,
4979,
10192,
2706,
21033,
1967,
2394,
14002,
10763,
7225,
1985,
7700,
2810,
1942,
4872,
6087,
4801,
43,
2535,
5284,
2706,
14002,
10763,
7225,
17,
2324,
1930,
16,
1942,
43,
11318,
4647,
16,
1985,
2810,
1942,
2502,
5944,
3257,
3389,
2706,
14002,
10763,
7225,
17,
44,
7225,
7225,
17,
44,
12,
18,
3020,
3201,
18,
18,
2369,
16,
2763,
31,
58,
33,
18,
26114,
16,
4967,
1958,
2632,
16,
12413,
5212,
16,
1930,
30082,
3050,
13,
18,
2144,
2230,
3220,
1988,
2342,
5556,
5184,
1927,
2502,
5043,
4979,
10192,
2706,
21033,
1967,
2394,
14002,
10763,
7225,
1985,
7700,
2810,
1942,
4872,
6087,
4801,
43,
2535,
5284,
2706,
14002,
10763,
7225,
17,
2324,
1930,
16,
1942,
43,
11318,
4647,
16,
1985,
2810,
1942,
2502,
5944,
3257,
3389,
2706,
14002,
10763,
7225,
17,
44,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
2,
2,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
7977356 | [
"High-resolution",
"linkage-disequilibrium",
"mapping",
"of",
"the",
"cartilage-hair",
"hypoplasia",
"gene.",
"We",
"recently",
"assigned",
"the",
"gene",
"for",
"an",
"autosomal",
"recessive",
"skeletal",
"dysplasia,",
"cartilage-hair",
"hypoplasia",
"(",
"CHH",
"),",
"to",
"9p21-p13",
"in",
"Finnish",
"and",
"Amish",
"families.",
"An",
"association",
"was",
"observed",
"between",
"CHH",
" ",
"and",
"alleles",
"at",
"D9S163",
"in",
"both",
"family",
"series,",
"suggesting",
"that",
"these",
"loci",
"are",
"in",
"linkage",
"disequilibrium",
"and",
"close",
"to",
"each",
"other.",
"Here",
"we",
"extended",
"these",
"studies",
"by",
"exploiting",
"the",
"linkage-disequilibrium",
"information",
"that",
"can",
"be",
"obtained",
"from",
"families",
"with",
"a",
"single",
"affected",
"child,",
"and",
"we",
"studied",
"66",
"Finnish",
"CHH",
" ",
"families",
"with",
"seven",
"microsatellite",
"markers.",
"The",
"analysis",
"based",
"on",
"the",
"Luria",
"and",
"Delbrück",
"(1943)",
"method",
"and",
"adapted",
"to",
"the",
"study",
"of",
"human",
"founder",
"populations",
"suggests",
"that",
"the",
"distance",
"between",
"CHH",
" ",
"and",
"D9S163",
"is",
"approximately",
"0.3",
"cM.",
"An",
"eight-point",
"linkage",
"analysis",
"modified",
"to",
"take",
"advantage",
"of",
"all",
"possible",
"information",
"in",
"15",
"Finnish",
"and",
"17",
"Amish",
"families",
"was",
"capable",
"of",
"narrowing",
"the",
"likely",
"location",
"of",
"CHH",
" ",
"to",
"within",
"an",
"interval",
"of",
"1.7",
"cM",
"on",
"a",
"male",
"map.",
"The",
"peak",
"lod",
"score",
"of",
"54.92",
"was",
"attained",
"0.03",
"and",
"0.1",
"cM",
"proximal",
"to",
"D9S163",
"on",
"the",
"male",
"and",
"female",
"maps,",
"respectively.",
"These",
"results",
"confirm",
"the",
"power",
"of",
"genetic",
"resolution,",
"that",
"lies",
"in",
"the",
"study",
"of",
"linkage",
"disequilibrium",
"in",
"well-defined",
"founder",
"populations",
"with",
"one",
"major",
"ancestral",
"disease",
"mutation."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | High-resolution linkage-disequilibrium mapping of the cartilage-hair hypoplasia gene. We recently assigned the gene for an autosomal recessive skeletal dysplasia, cartilage-hair hypoplasia ( CHH ), to 9p21-p13 in Finnish and Amish families. An association was observed between CHH and alleles at D9S163 in both family series, suggesting that these loci are in linkage disequilibrium and close to each other. Here we extended these studies by exploiting the linkage-disequilibrium information that can be obtained from families with a single affected child, and we studied 66 Finnish CHH families with seven microsatellite markers. The analysis based on the Luria and Delbrück (1943) method and adapted to the study of human founder populations suggests that the distance between CHH and D9S163 is approximately 0.3 cM. An eight-point linkage analysis modified to take advantage of all possible information in 15 Finnish and 17 Amish families was capable of narrowing the likely location of CHH to within an interval of 1.7 cM on a male map. The peak lod score of 54.92 was attained 0.03 and 0.1 cM proximal to D9S163 on the male and female maps, respectively. These results confirm the power of genetic resolution, that lies in the study of linkage disequilibrium in well-defined founder populations with one major ancestral disease mutation. | [
2,
2149,
17,
4885,
8611,
17,
19264,
7084,
1927,
1920,
8642,
17,
7018,
25502,
2359,
18,
2038,
3998,
6304,
1920,
2359,
1958,
1925,
13027,
13992,
7345,
14095,
16,
8642,
17,
7018,
25502,
12,
2016,
1023,
13,
16,
1942,
29,
5991,
1009,
17,
8632,
1010,
1922,
24016,
1930,
15665,
6150,
5767,
18,
1925,
3279,
1982,
2528,
2192,
2016,
1023,
1930,
7096,
2019,
46,
1026,
12030,
7576,
1922,
2321,
3416,
4696,
16,
3783,
1988,
2144,
6971,
2032,
1922,
8611,
19264,
1930,
5428,
1942,
2362,
2303,
18,
3410,
2038,
6091,
2144,
2351,
2007,
24096,
1920,
8611,
17,
19264,
2988,
1988,
2112,
1998,
2926,
2037,
5767,
1956,
43,
2957,
4218,
2748,
16,
1930,
2038,
3942,
4970,
24016,
2016,
1023,
5767,
1956,
5260,
16069,
4432,
18,
1920,
2333,
2454,
1990,
1920,
10908,
3027,
1019,
1930,
2723,
2377,
9764,
12,
17073,
1010,
13,
2417,
1930,
8461,
1942,
1920,
2161,
1927,
2616,
21350,
4098,
4015,
1988,
1920,
4819,
2192,
2016,
1023,
1930,
46,
1026,
12030,
7576,
1977,
3993,
20,
18,
23,
3195,
18,
1925,
5066,
17,
3575,
8611,
2333,
4795,
1942,
6132,
6607,
1927,
2136,
3216,
2988,
1922,
2461,
24016,
1930,
2752,
15665,
6150,
5767,
1982,
7131,
1927,
21005,
1920,
3205,
5185,
1927,
2016,
1023,
1942,
2651,
1925,
4979,
1927,
21,
18,
27,
3195,
1990,
43,
4005,
4446,
18,
1920,
3833,
15187,
3593,
1927,
4584,
18,
6224,
1982,
17346,
20,
18,
5167,
1930,
20,
18,
21,
3195,
6863,
1942,
46,
1026,
12030,
7576,
1990,
1920,
4005,
1930,
4232,
7422,
16,
2763,
18,
2144,
2274,
4763,
1920,
4215,
1927,
3299,
4885,
16,
1988,
13978,
1922,
1920,
2161,
1927,
8611,
19264,
1922,
2486,
17,
3608,
21350,
4098,
1956,
2340,
3044,
14417,
2573,
3979,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
21529752 | [
"The",
"essential",
"role",
"of",
"centrosomal",
"NDE1",
" ",
"in",
"human",
"cerebral",
"cortex",
"neurogenesis.",
"We",
"investigated",
"three",
"families",
"whose",
"offspring",
"had",
"extreme",
"microcephaly",
"at",
"birth",
"and",
"profound",
"mental",
"retardation.",
"Brain",
"scans",
"and",
"postmortem",
"data",
"showed",
"that",
"affected",
"individuals",
"had",
"brains",
"less",
"than",
"10%",
"of",
"expected",
"size",
"(≤10",
"standard",
"deviation)",
"and",
"that",
"in",
"addition",
"to",
"a",
"massive",
"reduction",
"in",
"neuron",
"production",
"they",
"displayed",
"partially",
"deficient",
"cortical",
"lamination",
"(microlissencephaly).",
"Other",
" ",
"body",
"systems",
"were",
"apparently",
"unaffected",
"and",
"overall",
"growth",
"was",
"normal.",
"We",
"found",
"two",
"distinct",
"homozygous",
"mutations",
"of",
"NDE1",
",",
"c.83+1G>T",
" ",
"(",
"p.Ala29GlnfsX114",
")",
"in",
"a",
"Turkish",
"family",
"and",
"c.684_685del",
" ",
"(",
"p.Pro229TrpfsX85",
")",
"in",
"two",
"families",
"of",
"Pakistani",
"origin.",
"Using",
"patient",
"cells,",
"we",
"found",
"that",
"c.83+1G>T",
" ",
"led",
"to",
"the",
"use",
"of",
"a",
"novel",
"splice",
"site",
"and",
"to",
"a",
"frameshift",
"after",
"NDE1",
" ",
"exon",
"2.",
"Transfection",
"of",
"tagged",
"NDE1",
" ",
"constructs",
"showed",
"that",
"the",
"c.684_685del",
" ",
"mutation",
"resulted",
"in",
"a",
"NDE1",
" ",
"that",
"was",
"unable",
"to",
"localize",
"to",
"the",
"centrosome.",
"By",
"staining",
"a",
"patient-derived",
"cell",
"line",
"that",
"carried",
"the",
"c.83+1G>T",
" ",
"mutation,",
"we",
"found",
"that",
"this",
"endogeneously",
"expressed",
"mutated",
"protein",
"equally",
"failed",
"to",
"localize",
"to",
"the",
"centrosome.",
"By",
"examining",
"human",
"and",
"mouse",
"embryonic",
"brains,",
"we",
"determined",
"that",
"NDE1",
" ",
"is",
"highly",
"expressed",
"in",
"neuroepithelial",
"cells",
"of",
"the",
"developing",
"cerebral",
"cortex,",
"particularly",
"at",
"the",
"centrosome.",
"We",
"show",
"that",
"NDE1",
" ",
"accumulates",
"on",
"the",
"mitotic",
"spindle",
"of",
"apical",
"neural",
"precursors",
"in",
"early",
"neurogenesis.",
"Thus,",
"NDE1",
" ",
"deficiency",
"causes",
"both",
"a",
"severe",
"failure",
"of",
"neurogenesis",
"and",
"a",
"deficiency",
"in",
"cortical",
"lamination.",
"Our",
"data",
"further",
"highlight",
"the",
"importance",
"of",
"the",
"centrosome",
"in",
"multiple",
"aspects",
"of",
"neurodevelopment."
] | [
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1 , c.83+1G>T ( p.Ala29GlnfsX114 ) in a Turkish family and c.684_685del ( p.Pro229TrpfsX85 ) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment. | [
2,
1920,
4415,
2770,
1927,
14783,
4229,
27594,
1009,
1922,
2616,
6329,
4997,
13967,
18,
2038,
3845,
2559,
5767,
6098,
9074,
2430,
9848,
10572,
2128,
7289,
1012,
2019,
5043,
1930,
11098,
5018,
16342,
18,
3068,
8581,
1930,
19411,
2230,
2594,
1988,
4218,
3445,
2430,
9831,
2941,
2254,
2119,
9,
1927,
4100,
3081,
12,
373,
2930,
2970,
6015,
13,
1930,
1988,
1922,
2459,
1942,
43,
12944,
3378,
1922,
7428,
3372,
2611,
5822,
6426,
5778,
5586,
14310,
1929,
12,
16262,
2348,
12217,
1012,
13,
18,
2303,
3362,
3771,
1985,
10535,
10403,
1930,
3399,
2905,
1982,
2791,
18,
2038,
2435,
2288,
4493,
9419,
3527,
1927,
27594,
1009,
16,
45,
18,
5893,
15,
15957,
34,
62,
12,
58,
18,
10527,
4539,
4365,
3938,
1036,
7653,
3745,
13,
1922,
43,
26928,
3416,
1930,
45,
18,
5117,
1006,
41,
5117,
1015,
16878,
12,
58,
18,
1965,
24570,
1997,
1034,
3544,
1039,
10025,
13,
1922,
2288,
5767,
1927,
21493,
1033,
4853,
18,
2193,
2774,
2094,
16,
2038,
2435,
1988,
45,
18,
5893,
15,
15957,
34,
62,
4866,
1942,
1920,
2485,
1927,
43,
4008,
10708,
3200,
1930,
1942,
43,
21848,
2256,
27594,
1009,
7049,
22,
18,
6496,
1927,
7896,
27594,
1009,
7220,
2594,
1988,
1920,
45,
18,
5117,
1006,
41,
5117,
1015,
16878,
3979,
4306,
1922,
43,
27594,
1009,
1988,
1982,
8082,
1942,
14380,
1942,
1920,
19959,
18,
2007,
4166,
43,
2774,
17,
3595,
2024,
2823,
1988,
4371,
1920,
45,
18,
5893,
15,
15957,
34,
62,
3979,
16,
2038,
2435,
1988,
2052,
16239,
14687,
8232,
3198,
8336,
2213,
9208,
6617,
1942,
14380,
1942,
1920,
19959,
18,
2007,
8469,
2616,
1930,
3321,
7231,
9831,
16,
2038,
3180,
1988,
27594,
1009,
1977,
3626,
3198,
1922,
3366,
14705,
2094,
1927,
1920,
5130,
6329,
4997,
16,
4443,
2019,
1920,
19959,
18,
2038,
2146,
1988,
27594,
1009,
18804,
1990,
1920,
9566,
10716,
1927,
8913,
5181,
10416,
1922,
3120,
13967,
18,
2842,
16,
27594,
1009,
6179,
5092,
2321,
43,
4010,
4574,
1927,
13967,
1930,
43,
6179,
1922,
5586,
14310,
1929,
18,
2342,
2230,
2520,
9159,
1920,
4737,
1927,
1920,
19959,
1922,
3137,
6082,
1927,
16597,
2017,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9634522 | [
"The",
"8765delAG",
" ",
"mutation",
"in",
"BRCA2",
" ",
"is",
"common",
"among",
"Jews",
"of",
"Yemenite",
"extraction."
] | [
0,
3,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0
] | The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. | [
2,
1920,
5783,
5964,
16878,
2006,
3979,
1922,
17845,
1977,
3059,
2706,
28296,
1036,
1927,
5293,
19047,
2394,
5914,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
3,
4,
4,
4,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
9683585 | [
"Germ-line",
"mutation",
"analysis",
"in",
"patients",
"with",
"multiple",
"endocrine",
"neoplasia",
"type",
"1",
"and",
"related",
"disorders.",
"Multiple",
"endocrine",
"neoplasia",
"type",
"1",
"(MEN1)",
"is",
"an",
"autosomal",
"dominant",
"syndrome",
"predisposing",
"to",
"tumors",
"of",
"the",
"parathyroid,",
"endocrine",
"pancreas,",
"anterior",
"pituitary,",
"adrenal",
"glands,",
"and",
"diffuse",
"neuroendocrine",
"tissues.",
"The",
"MEN1",
" ",
"gene",
"has",
"been",
"assigned,",
"by",
"linkage",
"analysis",
"and",
"loss",
"of",
"heterozygosity,",
"to",
"chromosome",
"11q13",
"and",
"recently",
"has",
"been",
"identified",
"by",
"positional",
"cloning.",
"In",
"this",
"study,",
"a",
"total",
"of",
"84",
"families",
"and/or",
"isolated",
"patients",
"with",
"either",
"MEN1",
" ",
"or",
"MEN1-related",
"inherited",
"endocrine",
"tumors",
"were",
"screened",
"for",
"MEN1",
"germ-line",
"mutations,",
"by",
"heteroduplex",
"and",
"sequence",
"analysis",
"of",
"the",
"MEN1",
" ",
"gene-coding",
"region",
"and",
"untranslated",
"exon",
"1.",
"Germ-line",
"MEN1",
" ",
"alterations",
"were",
"identified",
"in",
"47/54",
"(87%)",
"MEN1",
" ",
"families,",
"in",
"9/11",
"(82%)",
"isolated",
"MEN1",
" ",
"patients,",
"and",
"in",
"only",
"6/19",
"(31.5%)",
"atypical",
"MEN1-related",
"inherited",
"cases.",
"We",
"characterized",
"52",
"distinct",
"mutations",
"in",
"a",
"total",
"of",
"62",
"MEN1",
" ",
"germ-line",
"alterations.",
"Thirty-five",
"of",
"the",
"52",
"mutations",
"were",
"frameshifts",
"and",
"nonsense",
"mutations",
"predicted",
"to",
"encode",
"for",
"a",
"truncated",
"MEN1",
" ",
"protein.",
"We",
"identified",
"eight",
"missense",
"mutations",
"and",
"five",
"in-frame",
"deletions",
"over",
"the",
"entire",
"coding",
"sequence.",
"Six",
"mutations",
"were",
"observed",
"more",
"than",
"once",
"in",
"familial",
"MEN1.",
" ",
"Haplotype",
"analysis",
"in",
"families",
"with",
"identical",
"mutations",
"indicate",
"that",
"these",
"occurrences",
"reflected",
"mainly",
"independent",
"mutational",
"events.",
"No",
"MEN1",
" ",
"germ-line",
"mutations",
"were",
"found",
"in",
"7/54",
"(13%)",
"MEN1",
" ",
"families,",
"in",
"2/11",
"(18%)",
"isolated",
"MEN1",
" ",
"cases,",
"in",
"13/19",
"(68.",
"5%)",
"MEN1-related",
"cases,",
"and",
"in",
"a",
"kindred",
"with",
"familial",
"isolated",
"hyperparathyroidism.",
"Two",
"hundred",
"twenty",
"gene",
"carriers",
"(167",
"affected",
"and",
"53",
"unaffected)",
"were",
"identified.",
"No",
"evidence",
"of",
"genotype-phenotype",
"correlation",
"was",
"found.",
"Age-related",
"penetrance",
"was",
"estimated",
"to",
"be",
">95%",
"at",
"age",
">30",
"years.",
"Our",
"results",
"add",
"to",
"the",
"diversity",
"of",
"MEN1",
" ",
"germ-line",
"mutations",
"and",
"provide",
"new",
"tools",
"in",
"genetic",
"screening",
"of",
"MEN1",
" ",
"and",
"clinically",
"related",
"cases."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0
] | Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases. | [
2,
4363,
17,
2823,
3979,
2333,
1922,
2132,
1956,
3137,
10749,
17773,
2601,
21,
1930,
2712,
4414,
18,
3137,
10749,
17773,
2601,
21,
12,
3925,
1009,
13,
1977,
1925,
13027,
6379,
4741,
20908,
1942,
3861,
1927,
1920,
17152,
16,
10749,
10936,
16,
5477,
10621,
16,
10651,
11186,
16,
1930,
9435,
15980,
3878,
18,
1920,
3925,
1009,
2359,
2258,
2252,
6304,
16,
2007,
8611,
2333,
1930,
3257,
1927,
18896,
16,
1942,
5597,
2513,
16886,
1010,
1930,
3998,
2258,
2252,
2899,
2007,
20172,
11501,
18,
1922,
2052,
2161,
16,
43,
2698,
1927,
5686,
5767,
1930,
19,
2014,
3937,
2132,
1956,
3108,
3925,
1009,
2014,
3925,
1009,
17,
2712,
12911,
10749,
3861,
1985,
8582,
1958,
3925,
1009,
4363,
17,
2823,
3527,
16,
2007,
11330,
3481,
2592,
1930,
3244,
2333,
1927,
1920,
3925,
1009,
2359,
17,
5804,
3031,
1930,
19522,
7049,
21,
18,
4363,
17,
2823,
3925,
1009,
5996,
1985,
2899,
1922,
4261,
19,
4584,
12,
5783,
9,
13,
3925,
1009,
5767,
16,
1922,
29,
19,
2513,
12,
6175,
9,
13,
3937,
3925,
1009,
2132,
16,
1930,
1922,
2444,
26,
19,
2282,
12,
3470,
18,
25,
9,
13,
10834,
3925,
1009,
17,
2712,
12911,
2919,
18,
2038,
4378,
4764,
4493,
3527,
1922,
43,
2698,
1927,
5374,
3925,
1009,
4363,
17,
2823,
5996,
18,
9942,
17,
3628,
1927,
1920,
4764,
3527,
1985,
21848,
1036,
1930,
19605,
3527,
4396,
1942,
11107,
1958,
43,
9530,
3925,
1009,
2213,
18,
2038,
2899,
5066,
13519,
3527,
1930,
3628,
1922,
17,
7673,
10550,
2338,
1920,
5346,
5804,
3244,
18,
3798,
3527,
1985,
2528,
2253,
2254,
5361,
1922,
11444,
3925,
1009,
18,
10949,
2333,
1922,
5767,
1956,
6119,
3527,
3579,
1988,
2144,
21917,
8830,
4994,
3484,
13736,
3916,
18,
2239,
3925,
1009,
4363,
17,
2823,
3527,
1985,
2435,
1922,
27,
19,
4584,
12,
2590,
9,
13,
3925,
1009,
5767,
16,
1922,
22,
19,
2513,
12,
2654,
9,
13,
3937,
3925,
1009,
2919,
16,
1922,
2590,
19,
2282,
12,
5117,
18,
25,
9,
13,
3925,
1009,
17,
2712,
2919,
16,
1930,
1922,
43,
6925,
3510,
1956,
11444,
3937,
30247,
18,
2288,
8295,
7639,
2359,
8974,
12,
14997,
4218,
1930,
4522,
10403,
13,
1985,
2899,
18,
2239,
3095,
1927,
5619,
17,
4629,
3670,
1982,
2435,
18,
2632,
17,
2712,
22035,
1982,
4185,
1942,
1998,
34,
3002,
9,
2019,
2632,
34,
2627,
2739,
18,
2342,
2274,
3019,
1942,
1920,
5935,
1927,
3925,
1009,
4363,
17,
2823,
3527,
1930,
3394,
2814,
6257,
1922,
3299,
4449,
1927,
3925,
1009,
1930,
5908,
2712,
2919,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
-100
] |
1284538 | [
"Four",
"new",
"mutations",
"of",
"the",
"CFTR",
" ",
"gene",
"(",
"541delC",
",",
"R347H",
",",
"R352Q",
",",
"E585X",
")",
"detected",
"by",
"DGGE",
"analysis",
"in",
"Italian",
"CF",
"patients,",
"associated",
"with",
"different",
"clinical",
"phenotypes.",
"The",
"delta",
"508",
" ",
"mutation",
"accounts",
"for",
"about",
"53%",
"of",
"the",
"molecular",
"defects",
"causing",
"cystic",
"fibrosis",
"(CF)",
"in",
"Italy.",
"The",
"numerous",
"additional",
"mutations",
"detected",
"so",
"far",
"are",
"all",
"relatively",
"rare,",
"and",
"about",
"30%",
"of",
"CF",
"chromosomes",
"carries",
"unknown",
"mutations",
"in",
"our",
"patients.",
"In",
"order",
"to",
"identify",
"the",
"non-delta",
"F508",
" ",
"mutations",
"causing",
"CF",
"in",
"our",
"population,",
"we",
"performed",
"GC-clamped",
"denaturing",
"gradient",
"gel",
"electrophoresis",
"(DGGE)",
"on",
"9",
"exons",
"of",
"the",
"cystic",
"fibrosis",
"transmembrane",
"conductance",
"regulator",
" ",
"(",
"CFTR",
")",
"gene",
"in",
"a",
"sample",
"of",
"86",
"Italian",
"CF",
"patients",
"carrying",
"unknown",
"mutations",
"on",
"at",
"least",
"one",
"chromosome.",
"Direct",
"sequencing",
"of",
"17",
"samples",
"showing",
"an",
"altered",
"electrophoretic",
"mobility",
"allowed",
"the",
"identification",
"of",
"four",
"new",
"mutations",
"(",
"541delC",
",",
"R347H",
",",
"R352Q",
",",
"and",
"E585X",
"),",
"five",
"mutations",
"already",
"known",
"(",
"G85E",
",",
"I148T",
",",
"G178R",
",",
"1078delT",
",",
"and",
"R347P",
"),",
"and",
"one",
"rare",
"variant",
"(",
"1898",
"+",
"3A-->G",
").",
"The",
"strategy",
"based",
"on",
"GC-clamped",
"DGGE",
"represents",
"an",
"efficient",
"and",
"rapid",
"approach",
"for",
"mutation",
"detection",
"for",
"those",
"genetic",
"diseases,",
"such",
"as",
"CF,",
"in",
"which",
"a",
"large",
"number",
"of",
"rare",
"molecular",
"defects",
"has",
"been",
"described."
] | [
0,
0,
0,
0,
0,
1,
0,
0,
0,
3,
0,
3,
0,
3,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Four new mutations of the CFTR gene ( 541delC , R347H , R352Q , E585X ) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. The delta 508 mutation accounts for about 53% of the molecular defects causing cystic fibrosis (CF) in Italy. The numerous additional mutations detected so far are all relatively rare, and about 30% of CF chromosomes carries unknown mutations in our patients. In order to identify the non-delta F508 mutations causing CF in our population, we performed GC-clamped denaturing gradient gel electrophoresis (DGGE) on 9 exons of the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene in a sample of 86 Italian CF patients carrying unknown mutations on at least one chromosome. Direct sequencing of 17 samples showing an altered electrophoretic mobility allowed the identification of four new mutations ( 541delC , R347H , R352Q , and E585X ), five mutations already known ( G85E , I148T , G178R , 1078delT , and R347P ), and one rare variant ( 1898 + 3A-->G ). The strategy based on GC-clamped DGGE represents an efficient and rapid approach for mutation detection for those genetic diseases, such as CF, in which a large number of rare molecular defects has been described. | [
2,
3006,
2814,
3527,
1927,
1920,
13533,
2359,
12,
4584,
18737,
1938,
1030,
16,
19217,
6106,
1023,
16,
19217,
8982,
1055,
16,
28332,
10025,
1039,
13,
3330,
2007,
9665,
2106,
2333,
1922,
15922,
4920,
2132,
16,
2458,
1956,
2413,
2535,
6568,
18,
1920,
9649,
2761,
1025,
3979,
11053,
1958,
3001,
4522,
9,
1927,
1920,
3272,
6007,
7538,
11656,
6769,
12,
4920,
13,
1922,
12012,
18,
1920,
6466,
3281,
3527,
3330,
2577,
5108,
2032,
2136,
4322,
5844,
16,
1930,
3001,
2627,
9,
1927,
4920,
8597,
16252,
5435,
3527,
1922,
2342,
2132,
18,
1922,
3238,
1942,
3512,
1920,
2447,
17,
9649,
27221,
13895,
3527,
7538,
4920,
1922,
2342,
2973,
16,
2038,
2593,
5469,
17,
29935,
19013,
6494,
4669,
8633,
12,
9665,
2106,
13,
1990,
29,
10419,
1927,
1920,
11656,
6769,
9117,
11977,
7888,
12,
13533,
13,
2359,
1922,
43,
2983,
1927,
5713,
15922,
4920,
2132,
8215,
5435,
3527,
1990,
2019,
3464,
2340,
5597,
18,
3083,
4754,
1927,
2752,
2785,
4570,
1925,
5520,
18658,
8471,
5563,
1920,
4824,
1927,
3006,
2814,
3527,
12,
4584,
18737,
1938,
1030,
16,
19217,
6106,
1023,
16,
19217,
8982,
1055,
16,
1930,
28332,
10025,
1039,
13,
16,
3628,
3527,
6064,
3171,
12,
49,
10025,
1021,
16,
27926,
6301,
1031,
16,
8533,
7950,
1005,
16,
9176,
1025,
16878,
1031,
16,
1930,
19217,
6106,
1034,
13,
16,
1930,
2340,
5844,
6031,
12,
17120,
1025,
15,
5694,
17,
17,
34,
49,
13,
18,
1920,
4884,
2454,
1990,
5469,
17,
29935,
9665,
2106,
4972,
1925,
5807,
1930,
4052,
2998,
1958,
3979,
3805,
1958,
2690,
3299,
3902,
16,
2427,
1966,
4920,
16,
1922,
2154,
43,
3103,
2529,
1927,
5844,
3272,
6007,
2258,
2252,
2910,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
1,
0,
0,
3,
4,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
4,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
15714686 | [
"2004",
"William",
"Allan",
"Award",
"address.",
"Cloning",
"of",
"the",
"DMD",
" ",
"gene."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0
] | 2004 William Allan Award address. Cloning of the DMD gene. | [
2,
4247,
29578,
2136,
1928,
12125,
4640,
18,
11501,
1927,
1920,
20646,
2359,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
-100
] |
8352275 | [
"Linkage",
"analysis",
"of",
"idiopathic",
"generalized",
"epilepsy",
"(IGE)",
"and",
"marker",
"loci",
"on",
"chromosome",
"6p",
"in",
"families",
"of",
"patients",
"with",
"juvenile",
"myoclonic",
"epilepsy:",
"no",
"evidence",
"for",
"an",
"epilepsy",
"locus",
"in",
"the",
"HLA",
"region.",
"Evidence",
"for",
"a",
"locus",
"(",
"EJM1",
")",
"in",
"the",
"HLA",
"region",
"of",
"chromosome",
"6p",
"predisposing",
"to",
"idiopathic",
"generalized",
"epilepsy",
"(IGE)",
"in",
"the",
"families",
"of",
"patients",
"with",
"juvenile",
"myoclonic",
"epilepsy",
"(JME)",
"has",
"been",
"obtained",
"in",
"two",
"previous",
"studies",
"of",
"separately",
"ascertained",
"groups",
"of",
"kindreds.",
"Linkage",
"analysis",
"has",
"been",
"undertaken",
"in",
"a",
"third",
"set",
"of",
"25",
"families",
"including",
"a",
"patient",
"with",
"JME",
"and",
"at",
"least",
"one",
"first-degree",
"relative",
"with",
"IGE.",
"Family",
"members",
"were",
"typed",
"for",
"eight",
"polymorphic",
"loci",
"on",
"chromosome",
"6p:",
"F13A,",
"D6S89,",
"D6S109,",
"D6S105,",
"D6S10,",
"C4B,",
"DQA1/A2,",
"and",
"TCTE1",
"F13A",
",",
"D6S89",
",",
"D6S109",
",",
"D6S105",
",",
"D6S10",
",",
"C4B",
",",
"DQA1/A2",
",",
"and",
"TCTE1.",
"Pairwise",
"and",
"multipoint",
"linkage",
"analysis",
"was",
"carried",
"out",
"assuming",
"autosomal",
"dominant",
"and",
"autosomal",
"recessive",
"inheritance",
"and",
"age-dependent",
"high",
"or",
"low",
"penetrance.",
"No",
"significant",
"evidence",
"in",
"favor",
"of",
"linkage",
"was",
"obtained",
"at",
"any",
"locus.",
"Multipoint",
"linkage",
"analysis",
"generated",
"significant",
"exclusion",
"data",
"(lod",
"score",
"<",
"-2.0)",
"at",
"HLA",
"and",
"for",
"a",
"region",
"10-30",
"cM",
"telomeric",
"to",
"HLA,",
"the",
"extent",
"of",
"which",
"varied",
"with",
"the",
"level",
"of",
"penetrance",
"assumed.",
"These",
"observations",
"indicate",
"that",
"genetic",
"heterogeneity",
"exists",
"within",
"this",
"epilepsy",
"phenotype."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region. Evidence for a locus ( EJM1 ) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6S89, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1 F13A , D6S89 , D6S109 , D6S105 , D6S10 , C4B , DQA1/A2 , and TCTE1. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessive inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype. | [
2,
8611,
2333,
1927,
13513,
9612,
9741,
12,
10777,
13,
1930,
4966,
6971,
1990,
5597,
26,
1034,
1922,
5767,
1927,
2132,
1956,
13010,
15924,
2223,
3490,
9741,
30,
2239,
3095,
1958,
1925,
9741,
6730,
1922,
1920,
7225,
3031,
18,
3095,
1958,
43,
6730,
12,
16004,
8012,
13,
1922,
1920,
7225,
3031,
1927,
5597,
26,
1034,
20908,
1942,
13513,
9612,
9741,
12,
10777,
13,
1922,
1920,
5767,
1927,
2132,
1956,
13010,
15924,
2223,
3490,
9741,
12,
16097,
1021,
13,
2258,
2252,
2926,
1922,
2288,
2555,
2351,
1927,
7555,
19231,
2671,
1927,
6925,
3510,
1036,
18,
8611,
2333,
2258,
2252,
10466,
1922,
43,
4563,
2735,
1927,
2637,
5767,
2710,
43,
2774,
1956,
16097,
1021,
1930,
2019,
3464,
2340,
2561,
17,
4647,
3338,
1956,
10777,
18,
3416,
4678,
1985,
2601,
1007,
1958,
5066,
14240,
6971,
1990,
5597,
26,
1034,
30,
9154,
6675,
16,
15304,
1036,
9485,
16,
15304,
12030,
13192,
16,
15304,
12030,
15264,
16,
15304,
12030,
1008,
16,
10872,
1014,
16,
14750,
4904,
19,
8595,
16,
1930,
21939,
12474,
9154,
6675,
16,
15304,
1036,
9485,
16,
15304,
12030,
13192,
16,
15304,
12030,
15264,
16,
15304,
12030,
1008,
16,
10872,
1014,
16,
14750,
4904,
19,
8595,
16,
1930,
21939,
12474,
18,
10971,
1930,
20677,
4418,
8611,
2333,
1982,
4371,
2397,
10511,
13027,
6379,
1930,
13027,
13992,
15762,
1930,
2632,
17,
3100,
2149,
2014,
2330,
22035,
18,
2239,
2228,
3095,
1922,
7197,
1927,
8611,
1982,
2926,
2019,
2967,
6730,
18,
20677,
4418,
8611,
2333,
3999,
2228,
7901,
2230,
12,
15187,
3593,
32,
17,
22,
18,
20,
13,
2019,
7225,
1930,
1958,
43,
3031,
2119,
17,
2627,
3195,
19951,
1942,
7225,
16,
1920,
5064,
1927,
2154,
6760,
1956,
1920,
2237,
1927,
22035,
7696,
18,
2144,
5184,
3579,
1988,
3299,
6808,
8655,
2651,
2052,
9741,
4629,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
3,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
4,
0,
3,
4,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
18449911 | [
"Evaluation",
"of",
"in",
"silico",
"splice",
"tools",
"for",
"decision-making",
"in",
"molecular",
"diagnosis.",
"It",
"appears",
"that",
"all",
"types",
"of",
"genomic",
"nucleotide",
"variations",
"can",
"be",
"deleterious",
"by",
"affecting",
"normal",
"pre-mRNA",
"splicing",
"via",
"disruption/creation",
"of",
"splice",
"site",
"consensus",
"sequences.",
"As",
"it",
"is",
"neither",
"pertinent",
"nor",
"realistic",
"to",
"perform",
"functional",
"testing",
"for",
"all",
"of",
"these",
"variants,",
"it",
"is",
"important",
"to",
"identify",
"those",
"that",
"could",
"lead",
"to",
"a",
"splice",
"defect",
"in",
"order",
"to",
"restrict",
"transcript",
"analyses",
"to",
"the",
"most",
"appropriate",
"cases.",
"Web-based",
"tools",
"designed",
"to",
"provide",
"such",
"predictions",
"are",
"available.",
"We",
"evaluated",
"the",
"performance",
"of",
"six",
"of",
"these",
"tools",
"(Splice",
"Site",
"Prediction",
"by",
"Neural",
"Network",
"[NNSplice],",
"Splice-Site",
"Finder",
"[SSF],",
"MaxEntScan",
"[MES],",
"Automated",
"Splice-Site",
"Analyses",
"[ASSA],",
"Exonic",
"Splicing",
"Enhancer",
"[ESE]",
"Finder,",
"and",
"Relative",
"Enhancer",
"and",
"Silencer",
"Classification",
"by",
"Unanimous",
"Enrichment",
"[RESCUE]-ESE)",
"using",
"39",
"unrelated",
"retinoblastoma",
"patients",
"carrying",
"different",
"RB1",
"variants",
"(31",
"intronic",
"and",
"eight",
"exonic).",
"These",
"39",
"patients",
"were",
"screened",
"for",
"abnormal",
"splicing",
"using",
"puromycin-treated",
"cell",
"lines",
"and",
"the",
"results",
"were",
"compared",
"to",
"the",
"predictions.",
"As",
"expected,",
"17",
"variants",
"impacting",
"canonical",
"AG/GT",
"splice",
"sites",
"were",
"correctly",
"predicted",
"as",
"deleterious.",
"A",
"total",
"of",
"22",
"variations",
"occurring",
"at",
"loosely",
"defined",
"positions",
"(+/-60",
"nucleotides",
"from",
"an",
"AG/GT",
"site)",
"led",
"to",
"a",
"splice",
"defect",
"in",
"19",
"cases",
"and",
"16",
"of",
"them",
"were",
"classified",
"as",
"deleterious",
"by",
"at",
"least",
"one",
"tool",
"(84%",
"sensitivity).",
"In",
"other",
"words,",
"three",
"variants",
"escaped",
"in",
"silico",
"detection",
"and",
"the",
"remaining",
"three",
"were",
"correctly",
"predicted",
"as",
"neutral.",
"Overall",
"our",
"results",
"suggest",
"that",
"a",
"combination",
"of",
"complementary",
"in",
"silico",
"tools",
"is",
"necessary",
"to",
"guide",
"molecular",
"geneticists",
"(balance",
"between",
"the",
"time",
"and",
"cost",
"required",
"by",
"RNA",
"analysis",
"and",
"the",
"risk",
"of",
"missing",
"a",
"deleterious",
"mutation)",
"because",
"the",
"weaknesses",
"of",
"one",
"in",
"silico",
"tool",
"may",
"be",
"overcome",
"by",
"the",
"results",
"of",
"another",
"tool."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Evaluation of in silico splice tools for decision-making in molecular diagnosis. It appears that all types of genomic nucleotide variations can be deleterious by affecting normal pre-mRNA splicing via disruption/creation of splice site consensus sequences. As it is neither pertinent nor realistic to perform functional testing for all of these variants, it is important to identify those that could lead to a splice defect in order to restrict transcript analyses to the most appropriate cases. Web-based tools designed to provide such predictions are available. We evaluated the performance of six of these tools (Splice Site Prediction by Neural Network [NNSplice], Splice-Site Finder [SSF], MaxEntScan [MES], Automated Splice-Site Analyses [ASSA], Exonic Splicing Enhancer [ESE] Finder, and Relative Enhancer and Silencer Classification by Unanimous Enrichment [RESCUE]-ESE) using 39 unrelated retinoblastoma patients carrying different RB1 variants (31 intronic and eight exonic). These 39 patients were screened for abnormal splicing using puromycin-treated cell lines and the results were compared to the predictions. As expected, 17 variants impacting canonical AG/GT splice sites were correctly predicted as deleterious. A total of 22 variations occurring at loosely defined positions (+/-60 nucleotides from an AG/GT site) led to a splice defect in 19 cases and 16 of them were classified as deleterious by at least one tool (84% sensitivity). In other words, three variants escaped in silico detection and the remaining three were correctly predicted as neutral. Overall our results suggest that a combination of complementary in silico tools is necessary to guide molecular geneticists (balance between the time and cost required by RNA analysis and the risk of missing a deleterious mutation) because the weaknesses of one in silico tool may be overcome by the results of another tool. | [
2,
4391,
1927,
1922,
14270,
10708,
6257,
1958,
5534,
17,
5399,
1922,
3272,
3574,
18,
2176,
5107,
1988,
2136,
3584,
1927,
4935,
5489,
6740,
2112,
1998,
12524,
2007,
7359,
2791,
2097,
17,
3616,
8490,
3454,
7561,
19,
13874,
1927,
10708,
3200,
7076,
3709,
18,
1966,
2176,
1977,
7132,
20555,
3990,
14829,
1942,
2385,
3183,
4213,
1958,
2136,
1927,
2144,
4936,
16,
2176,
1977,
2715,
1942,
3512,
2690,
1988,
2578,
2949,
1942,
43,
10708,
7374,
1922,
3238,
1942,
18240,
5291,
3247,
1942,
1920,
2501,
4703,
2919,
18,
8391,
17,
2454,
6257,
4609,
1942,
3394,
2427,
8677,
2032,
3322,
18,
2038,
3747,
1920,
3604,
1927,
3798,
1927,
2144,
6257,
12,
10708,
3200,
5882,
2007,
5181,
3504,
37,
11450,
3508,
3742,
1021,
39,
16,
10708,
17,
3200,
5387,
1915,
37,
4577,
1038,
39,
16,
7531,
2039,
8337,
37,
4438,
39,
16,
9210,
10708,
17,
3200,
3247,
37,
2088,
1019,
39,
16,
29070,
8490,
10992,
37,
2376,
1021,
39,
5387,
1915,
16,
1930,
3338,
10992,
1930,
24974,
1005,
5492,
2007,
26844,
8635,
12492,
1957,
7298,
37,
10162,
39,
17,
2376,
1021,
13,
2193,
3886,
10295,
25526,
2132,
8215,
2413,
24460,
4936,
12,
3470,
20341,
1930,
5066,
29070,
13,
18,
2144,
3886,
2132,
1985,
8582,
1958,
4552,
8490,
2193,
19750,
17,
2868,
2024,
3557,
1930,
1920,
2274,
1985,
2452,
1942,
1920,
8677,
18,
1966,
4100,
16,
2752,
4936,
24677,
9452,
2260,
19,
4637,
10708,
3402,
1985,
10329,
4396,
1966,
12524,
18,
43,
2698,
1927,
2950,
6740,
6966,
2019,
27894,
3608,
6490,
12,
15,
19,
17,
3276,
9519,
2037,
1925,
2260,
19,
4637,
3200,
13,
4866,
1942,
43,
10708,
7374,
1922,
2282,
2919,
1930,
2641,
1927,
3581,
1985,
5947,
1966,
12524,
2007,
2019,
3464,
2340,
5229,
12,
5686,
9,
3802,
13,
18,
1922,
2303,
6906,
16,
2559,
4936,
11781,
1007,
1922,
14270,
3805,
1930,
1920,
5719,
2559,
1985,
10329,
4396,
1966,
5459,
18,
3399,
2342,
2274,
3220,
1988,
43,
3921,
1927,
8862,
1922,
14270,
6257,
1977,
4680,
1942,
7857,
3272,
3299,
3535,
12,
6766,
2192,
1920,
2367,
1930,
4455,
3414,
2007,
3146,
2333,
1930,
1920,
2565,
1927,
6814,
43,
12524,
3979,
13,
2882,
1920,
25367,
1927,
2340,
1922,
14270,
5229,
2278,
1998,
9063,
2007,
1920,
2274,
1927,
3741,
5229,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8023855 | [
"Small",
"marker",
"X",
"chromosomes",
"lack",
"the",
"X",
"inactivation",
"center:",
"implications",
"for",
"karyotype/phenotype",
"correlations.",
"The",
"abnormal",
"phenotype",
"and/or",
"mental",
"retardation",
"seen",
"in",
"persons",
"with",
"small",
"marker",
"X",
"(mar(X))",
"chromosomes",
"has",
"been",
"hypothesized",
"to",
"be",
"due",
"to",
"the",
"loss",
"of",
"the",
"X",
"inactivation",
"center",
"(XIC)",
"at",
"Xq13.2,",
"resulting",
"in",
"two",
"active",
"copies",
"of",
"genes",
"in",
"the",
"pericentromeric",
"region.",
"In",
"order",
"to",
"define",
"precisely",
"the",
"DNA",
"content",
"of",
"mar(X)",
"chromosomes",
"and",
"to",
"correlate",
"phenotype",
"with",
"karyotype,",
"we",
"studied",
"small",
"mar(X)",
"chromosomes,",
"using",
"FISH",
"with",
"probes",
"in",
"the",
"juxtacentromeric",
"region.",
"One",
"of",
"the",
"probes",
"was",
"a",
"40-kb",
"genomic",
"cosmid",
"for",
"the",
"XIST",
" ",
"gene,",
"which",
"maps",
"to",
"the",
"smallest",
"interval",
"known",
"to",
"contain",
"the",
"XIC",
"and",
"is",
"thought",
"to",
"be",
"involved",
"in",
"X",
"inactivation.",
"Our",
"findings",
"reveal",
"that",
"small",
"mar(X)",
"chromosomes",
"do",
"not",
"include",
"the",
"XIC",
"and",
"therefore",
"cannot",
"be",
"subject",
"to",
"X",
"inactivation,",
"supporting",
"the",
"premise",
"that",
"abnormal",
"dosage",
"of",
"expressed",
"genes",
"in",
"the",
"pericentromeric",
"region",
"of",
"the",
"X",
"generates",
"the",
"aberrant",
"phenotype",
"seen",
"in",
"patients",
"with",
"small",
"mar(X)",
"chromosomes."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Small marker X chromosomes lack the X inactivation center: implications for karyotype/phenotype correlations. The abnormal phenotype and/or mental retardation seen in persons with small marker X (mar(X)) chromosomes has been hypothesized to be due to the loss of the X inactivation center (XIC) at Xq13.2, resulting in two active copies of genes in the pericentromeric region. In order to define precisely the DNA content of mar(X) chromosomes and to correlate phenotype with karyotype, we studied small mar(X) chromosomes, using FISH with probes in the juxtacentromeric region. One of the probes was a 40-kb genomic cosmid for the XIST gene, which maps to the smallest interval known to contain the XIC and is thought to be involved in X inactivation. Our findings reveal that small mar(X) chromosomes do not include the XIC and therefore cannot be subject to X inactivation, supporting the premise that abnormal dosage of expressed genes in the pericentromeric region of the X generates the aberrant phenotype seen in patients with small mar(X) chromosomes. | [
2,
2858,
4966,
66,
8597,
3630,
1920,
66,
8005,
4102,
30,
7020,
1958,
21954,
19,
4629,
6100,
18,
1920,
4552,
4629,
1930,
19,
2014,
5018,
16342,
3945,
1922,
7618,
1956,
2858,
4966,
66,
12,
3684,
12,
66,
13,
13,
8597,
2258,
2252,
7149,
1942,
1998,
2810,
1942,
1920,
3257,
1927,
1920,
66,
8005,
4102,
12,
11551,
1030,
13,
2019,
66,
16886,
1010,
18,
22,
16,
3864,
1922,
2288,
3500,
9425,
1927,
2628,
1922,
1920,
10796,
2334,
8462,
3031,
18,
1922,
3238,
1942,
7425,
12565,
1920,
2678,
3919,
1927,
3684,
12,
66,
13,
8597,
1930,
1942,
8474,
4629,
1956,
21954,
16,
2038,
3942,
2858,
3684,
12,
66,
13,
8597,
16,
2193,
5724,
1956,
6885,
1922,
1920,
21887,
6672,
4191,
3133,
3031,
18,
2340,
1927,
1920,
6885,
1982,
43,
3040,
17,
6633,
4935,
28023,
1960,
1958,
1920,
29300,
2359,
16,
2154,
7422,
1942,
1920,
14274,
4979,
3171,
1942,
5531,
1920,
11551,
1030,
1930,
1977,
6212,
1942,
1998,
3286,
1922,
66,
8005,
18,
2342,
3056,
3157,
1988,
2858,
3684,
12,
66,
13,
8597,
2608,
2084,
3951,
1920,
11551,
1030,
1930,
2955,
5156,
1998,
5198,
1942,
66,
8005,
16,
6184,
1920,
26720,
1988,
4552,
9998,
1927,
3198,
2628,
1922,
1920,
10796,
2334,
8462,
3031,
1927,
1920,
66,
12399,
1920,
9801,
4629,
3945,
1922,
2132,
1956,
2858,
3684,
12,
66,
13,
8597,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
22770979 | [
"Presence",
"of",
"multiple",
"independent",
"effects",
"in",
"risk",
"loci",
"of",
"common",
"complex",
"human",
"diseases.",
"Many",
"genetic",
"loci",
"and",
"SNPs",
"associated",
"with",
"many",
"common",
"complex",
"human",
"diseases",
"and",
"traits",
"are",
"now",
"identified.",
"The",
"total",
"genetic",
"variance",
"explained",
"by",
"these",
"loci",
"for",
"a",
"trait",
"or",
"disease,",
"however,",
"has",
"often",
"been",
"very",
"small.",
"Much",
"of",
"the",
"\"missing",
"heritability\"",
"has",
"been",
"revealed",
"to",
"be",
"hidden",
"in",
"the",
"genome",
"among",
"the",
"large",
"number",
"of",
"variants",
"with",
"small",
"effects.",
"Several",
"recent",
"studies",
"have",
"reported",
"the",
"presence",
"of",
"multiple",
"independent",
"SNPs",
"and",
"genetic",
"heterogeneity",
"in",
"trait-associated",
"loci.",
"It",
"is",
"therefore",
"reasonable",
"to",
"speculate",
"that",
"such",
"a",
"phenomenon",
"could",
"be",
"common",
"among",
"loci",
"known",
"to",
"be",
"associated",
"with",
"a",
"complex",
"trait",
"or",
"disease.",
"For",
"testing",
"this",
"hypothesis,",
"a",
"total",
"of",
"117",
"loci",
"known",
"to",
"be",
"associated",
"with",
"rheumatoid",
"arthritis",
"(RA),",
"Crohn",
"disease",
"(CD),",
"type",
"1",
"diabetes",
"(T1D),",
"or",
"type",
"2",
"diabetes",
"(T2D)",
"were",
"selected.",
"The",
"presence",
"of",
"multiple",
"independent",
"effects",
"was",
"assessed",
"in",
"the",
"case-control",
"samples",
"genotyped",
"by",
"the",
"Wellcome",
"Trust",
"Case",
"Control",
"Consortium",
"study",
"and",
"imputed",
"with",
"SNP",
"genotype",
"information",
"from",
"the",
"HapMap",
"Project",
"and",
"the",
"1000",
"Genomes",
"Project.",
"Eleven",
"loci",
"with",
"evidence",
"of",
"multiple",
"independent",
"effects",
"were",
"identified",
"in",
"the",
"study,",
"and",
"the",
"number",
"was",
"expected",
"to",
"increase",
"at",
"larger",
"sample",
"sizes",
"and",
"improved",
"statistical",
"power.",
"The",
"variance",
"explained",
"by",
"the",
"multiple",
"effects",
"in",
"a",
"locus",
"was",
"much",
"higher",
"than",
"the",
"variance",
"explained",
"by",
"the",
"single",
"reported",
"SNP",
"effect.",
"The",
"results",
"thus",
"significantly",
"improve",
"our",
"understanding",
"of",
"the",
"allelic",
"structure",
"of",
"these",
"individual",
"disease-associated",
"loci,",
"as",
"well",
"as",
"our",
"knowledge",
"of",
"the",
"general",
"genetic",
"mechanisms",
"of",
"common",
"complex",
"traits",
"and",
"diseases."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Presence of multiple independent effects in risk loci of common complex human diseases. Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases. | [
2,
2990,
1927,
3137,
3484,
2564,
1922,
2565,
6971,
1927,
3059,
2796,
2616,
3902,
18,
3086,
3299,
6971,
1930,
6084,
2458,
1956,
3086,
3059,
2796,
2616,
3902,
1930,
7226,
2032,
5195,
2899,
18,
1920,
2698,
3299,
5623,
6094,
2007,
2144,
6971,
1958,
43,
8823,
2014,
2573,
16,
2406,
16,
2258,
3868,
2252,
3345,
2858,
18,
4186,
1927,
1920,
6,
6814,
16988,
6,
2258,
2252,
3404,
1942,
1998,
14878,
1922,
1920,
3843,
2706,
1920,
3103,
2529,
1927,
4936,
1956,
2858,
2564,
18,
2980,
3505,
2351,
2162,
2568,
1920,
2990,
1927,
3137,
3484,
6084,
1930,
3299,
6808,
1922,
8823,
17,
2458,
6971,
18,
2176,
1977,
2955,
9368,
1942,
12322,
1988,
2427,
43,
7902,
2578,
1998,
3059,
2706,
6971,
3171,
1942,
1998,
2458,
1956,
43,
2796,
8823,
2014,
2573,
18,
1958,
4213,
2052,
4676,
16,
43,
2698,
1927,
11678,
6971,
3171,
1942,
1998,
2458,
1956,
13053,
8884,
12,
4313,
13,
16,
17563,
2573,
12,
2464,
13,
16,
2601,
21,
4032,
12,
18139,
13,
16,
2014,
2601,
22,
4032,
12,
14736,
13,
1985,
3790,
18,
1920,
2990,
1927,
3137,
3484,
2564,
1982,
3683,
1922,
1920,
3087,
17,
2285,
2785,
14401,
2007,
1920,
21739,
10626,
3087,
2285,
14056,
2161,
1930,
19755,
1956,
6821,
5619,
2988,
2037,
1920,
26249,
5539,
1930,
1920,
5672,
7313,
5539,
18,
14483,
6971,
1956,
3095,
1927,
3137,
3484,
2564,
1985,
2899,
1922,
1920,
2161,
16,
1930,
1920,
2529,
1982,
4100,
1942,
2760,
2019,
4327,
2983,
6562,
1930,
4305,
3850,
4215,
18,
1920,
5623,
6094,
2007,
1920,
3137,
2564,
1922,
43,
6730,
1982,
4186,
2580,
2254,
1920,
5623,
6094,
2007,
1920,
2957,
2568,
6821,
2495,
18,
1920,
2274,
2842,
2567,
3326,
2342,
4339,
1927,
1920,
13045,
3170,
1927,
2144,
2725,
2573,
17,
2458,
6971,
16,
1966,
2486,
1966,
2342,
4163,
1927,
1920,
3335,
3299,
3531,
1927,
3059,
2796,
7226,
1930,
3902,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20506408 | [
"Functionality",
"of",
"sequence",
"variants",
"in",
"the",
"genes",
"coding",
"for",
"the",
"low-density",
"lipoprotein",
"receptor",
"and",
"apolipoprotein",
"B",
"in",
"individuals",
"with",
"inherited",
"hypercholesterolemia.",
"Patients",
"with",
"familial",
"hypercholesterolemia",
"(FH)",
"have",
"elevated",
"LDL-C",
"levels,",
"usually",
"above",
"the",
"90th",
"percentile",
"(P90)",
"for",
"age",
"and",
"gender.",
"However,",
"large-scale",
"genetic",
"cascade",
"screening",
"for",
"FH",
"showed",
"that",
"15%",
"of",
"the",
"LDL-receptor",
"(",
"LDLR",
")",
"or",
"Apolipoprotein",
"B",
"(",
"APOB",
"LDL-receptor",
" ",
"(LDLR)",
"or",
"Apolipoprotein",
"B",
" ",
"(APOB)",
"mutation",
"carriers",
"have",
"LDL-C",
"levels",
"below",
"P75.",
"Nonpathogenicity",
"of",
"sequence",
"changes",
"may",
"explain",
"this",
"phenomenon.",
"To",
"assess",
"pathogenicity",
"of",
"a",
"mutation",
"we",
"proposed",
"three",
"criteria:",
"(1)",
"mean",
"LDL-C",
"4P75",
"in",
"untreated",
"mutation",
"carriers;",
"(2)",
"higher",
"mean",
"LDL-C",
"level",
"in",
"untreated",
"carriers",
"than",
"in",
"untreated",
"noncarriers;",
"and",
"(3)",
"higher",
"percentage",
"of",
"medication",
"users",
"in",
"carriers",
"than",
"in",
"noncarriers",
"at",
"screening.",
"We",
"considered",
"a",
"mutation",
"nonpathogenic",
"when",
"none",
"of",
"the",
"three",
"criteria",
"were",
"met.",
"We",
"applied",
"these",
"criteria",
"to",
"mutations",
"that",
"had",
"been",
"determined",
"in",
"more",
"than",
"50",
"untreated",
"adults.",
"Segregation",
"analysis",
"was",
"performed",
"to",
"confirm",
"nonpathogenicity.",
"Forty-six",
"mutations",
"had",
"been",
"tested",
"in",
"more",
"than",
"50",
"untreated",
"subjects,",
"and",
"three",
"were",
"nonpathogenic",
"according",
"to",
"our",
"criteria:",
"one",
"in",
"LDLR",
" ",
"(",
"c.108C4A",
",",
"exon",
"2)",
"and",
"two",
"in",
"APOB",
" ",
"(",
"c.13154T4C",
" ",
"and",
"c.13181T4C",
",",
"both",
"in",
"exon",
"29).",
"Segregation",
"analysis",
"also",
"indicated",
"nonpathogenicity.",
"According",
"to",
"our",
"criteria,",
"three",
"sequence",
"variants",
"were",
"nonpathogenic.",
"The",
"criteria",
"may",
"help",
"to",
"identify",
"nonpathogenic",
"sequence",
"changes",
"in",
"genetic",
"cascade",
"screening",
"programs."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
1,
1,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
3,
0,
0,
0,
0,
0,
0,
1,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. Patients with familial hypercholesterolemia (FH) have elevated LDL-C levels, usually above the 90th percentile (P90) for age and gender. However, large-scale genetic cascade screening for FH showed that 15% of the LDL-receptor ( LDLR ) or Apolipoprotein B ( APOB LDL-receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL-C levels below P75. Nonpathogenicity of sequence changes may explain this phenomenon. To assess pathogenicity of a mutation we proposed three criteria: (1) mean LDL-C 4P75 in untreated mutation carriers; (2) higher mean LDL-C level in untreated carriers than in untreated noncarriers; and (3) higher percentage of medication users in carriers than in noncarriers at screening. We considered a mutation nonpathogenic when none of the three criteria were met. We applied these criteria to mutations that had been determined in more than 50 untreated adults. Segregation analysis was performed to confirm nonpathogenicity. Forty-six mutations had been tested in more than 50 untreated subjects, and three were nonpathogenic according to our criteria: one in LDLR ( c.108C4A , exon 2) and two in APOB ( c.13154T4C and c.13181T4C , both in exon 29). Segregation analysis also indicated nonpathogenicity. According to our criteria, three sequence variants were nonpathogenic. The criteria may help to identify nonpathogenic sequence changes in genetic cascade screening programs. | [
2,
12315,
1927,
3244,
4936,
1922,
1920,
2628,
5804,
1958,
1920,
2330,
17,
3824,
9694,
3148,
1930,
18747,
44,
1922,
3445,
1956,
12911,
22862,
18,
2132,
1956,
11444,
22862,
12,
11912,
13,
2162,
4664,
8017,
17,
45,
2428,
16,
5394,
3538,
1920,
3865,
1963,
12163,
12,
58,
5124,
13,
1958,
2632,
1930,
5125,
18,
2406,
16,
3103,
17,
3536,
3299,
9861,
4449,
1958,
11912,
2594,
1988,
2461,
9,
1927,
1920,
8017,
17,
3148,
12,
20944,
13,
2014,
18747,
44,
12,
16349,
8017,
17,
3148,
12,
20944,
13,
2014,
18747,
44,
12,
16349,
13,
3979,
8974,
2162,
8017,
17,
45,
2428,
4535,
20111,
18,
24857,
2183,
12758,
1927,
3244,
2840,
2278,
5895,
2052,
7902,
18,
1942,
2634,
15903,
1927,
43,
3979,
2038,
4211,
2559,
4164,
30,
12,
21,
13,
2667,
8017,
17,
45,
24,
1034,
8245,
1922,
6829,
3979,
8974,
31,
12,
22,
13,
2580,
2667,
8017,
17,
45,
2237,
1922,
6829,
8974,
2254,
1922,
6829,
9341,
3994,
8885,
31,
1930,
12,
23,
13,
2580,
4466,
1927,
6093,
6603,
1922,
8974,
2254,
1922,
9341,
3994,
8885,
2019,
4449,
18,
2038,
3311,
43,
3979,
24857,
2183,
3880,
2469,
6046,
1927,
1920,
2559,
4164,
1985,
2130,
18,
2038,
3730,
2144,
4164,
1942,
3527,
1988,
2430,
2252,
3180,
1922,
2253,
2254,
2761,
6829,
4440,
18,
12707,
2333,
1982,
2593,
1942,
4763,
24857,
2183,
12758,
18,
11270,
17,
3798,
3527,
2430,
2252,
3620,
1922,
2253,
2254,
2761,
6829,
3297,
16,
1930,
2559,
1985,
24857,
2183,
3880,
3147,
1942,
2342,
4164,
30,
2340,
1922,
20944,
12,
45,
18,
9123,
17875,
1019,
16,
7049,
22,
13,
1930,
2288,
1922,
16349,
12,
45,
18,
11389,
5651,
1031,
25077,
1930,
45,
18,
11389,
11425,
1031,
25077,
16,
2321,
1922,
7049,
3230,
13,
18,
12707,
2333,
2222,
3391,
24857,
2183,
12758,
18,
3147,
1942,
2342,
4164,
16,
2559,
3244,
4936,
1985,
24857,
2183,
3880,
18,
1920,
4164,
2278,
4087,
1942,
3512,
24857,
2183,
3880,
3244,
2840,
1922,
3299,
9861,
4449,
6144,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
1,
1,
2,
2,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
1,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
12384858 | [
"The",
"fingerprint",
"of",
"phantom",
"mutations",
"in",
"mitochondrial",
"DNA",
"data.",
"Phantom",
"mutations",
"are",
"systematic",
"artifacts",
"generated",
"in",
"the",
"course",
"of",
"the",
"sequencing",
"process",
"itself.",
"In",
"sequenced",
"mitochondrial",
"DNA",
"(mtDNA),",
"they",
"generate",
"a",
"hotspot",
"pattern",
"quite",
"different",
"from",
"that",
"of",
"natural",
"mutations",
"in",
"the",
"cell.",
"To",
"identify",
"the",
"telltale",
"patterns",
"of",
"a",
"particular",
"phantom",
"mutation",
"process,",
"one",
"first",
"filters",
"out",
"the",
"well-established",
"frequent",
"mutations",
"(inferred",
"from",
"various",
"data",
"sets",
"with",
"additional",
"coding",
"region",
"information).",
"The",
"filtered",
"data",
"are",
"represented",
"by",
"their",
"full",
"(quasi-)median",
"network,",
"to",
"visualize",
"the",
"character",
"conflicts,",
"which",
"can",
"be",
"expressed",
"numerically",
"by",
"the",
"cube",
"spectrum.",
"Permutation",
"tests",
"are",
"used",
"to",
"evaluate",
"the",
"overall",
"phylogenetic",
"content",
"of",
"the",
"filtered",
"data.",
"Comparison",
"with",
"benchmark",
"data",
"sets",
"helps",
"to",
"sort",
"out",
"suspicious",
"data",
"and",
"to",
"infer",
"features",
"and",
"potential",
"causes",
"for",
"the",
"phantom",
"mutation",
"process.",
"This",
"approach,",
"performed",
"either",
"in",
"the",
"lab",
"or",
"at",
"the",
"desk",
"of",
"a",
"reviewer,",
"will",
"help",
"to",
"avoid",
"errors",
"that",
"otherwise",
"would",
"go",
"into",
"print",
"and",
"could",
"lead",
"to",
"erroneous",
"evolutionary",
"interpretations.",
"The",
"filtering",
"procedure",
"is",
"illustrated",
"with",
"two",
"mtDNA",
"data",
"sets",
"that",
"were",
"severely",
"affected",
"by",
"phantom",
"mutations."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | The fingerprint of phantom mutations in mitochondrial DNA data. Phantom mutations are systematic artifacts generated in the course of the sequencing process itself. In sequenced mitochondrial DNA (mtDNA), they generate a hotspot pattern quite different from that of natural mutations in the cell. To identify the telltale patterns of a particular phantom mutation process, one first filters out the well-established frequent mutations (inferred from various data sets with additional coding region information). The filtered data are represented by their full (quasi-)median network, to visualize the character conflicts, which can be expressed numerically by the cube spectrum. Permutation tests are used to evaluate the overall phylogenetic content of the filtered data. Comparison with benchmark data sets helps to sort out suspicious data and to infer features and potential causes for the phantom mutation process. This approach, performed either in the lab or at the desk of a reviewer, will help to avoid errors that otherwise would go into print and could lead to erroneous evolutionary interpretations. The filtering procedure is illustrated with two mtDNA data sets that were severely affected by phantom mutations. | [
2,
1920,
25004,
1927,
12159,
3527,
1922,
4596,
2678,
2230,
18,
12159,
3527,
2032,
5614,
13166,
3999,
1922,
1920,
4914,
1927,
1920,
4754,
2585,
6999,
18,
1922,
8549,
4596,
2678,
12,
11183,
13,
16,
2611,
5655,
43,
24225,
3114,
8288,
2413,
2037,
1988,
1927,
4613,
3527,
1922,
1920,
2024,
18,
1942,
3512,
1920,
17812,
2381,
1021,
4147,
1927,
43,
3278,
12159,
3979,
2585,
16,
2340,
2561,
11732,
2397,
1920,
2486,
17,
4379,
6439,
3527,
12,
11965,
2037,
3425,
2230,
5704,
1956,
3281,
5804,
3031,
2988,
13,
18,
1920,
8763,
2230,
2032,
5960,
2007,
2310,
4125,
12,
16317,
17,
13,
4181,
3504,
16,
1942,
13159,
1920,
2728,
14306,
16,
2154,
2112,
1998,
3198,
21409,
2007,
1920,
29426,
5648,
18,
19110,
4026,
2032,
2251,
1942,
4323,
1920,
3399,
7371,
3919,
1927,
1920,
8763,
2230,
18,
3723,
1956,
14911,
2230,
5704,
12612,
1942,
17362,
2397,
22488,
2230,
1930,
1942,
5201,
4075,
1930,
2889,
5092,
1958,
1920,
12159,
3979,
2585,
18,
2052,
2998,
16,
2593,
3108,
1922,
1920,
2857,
2014,
2019,
1920,
2270,
1040,
1927,
43,
18124,
16,
2832,
4087,
1942,
5161,
6109,
1988,
7631,
2962,
3611,
2460,
21793,
1930,
2578,
2949,
1942,
26174,
8118,
19178,
18,
1920,
12433,
4360,
1977,
9125,
1956,
2288,
11183,
2230,
5704,
1988,
1985,
10561,
4218,
2007,
12159,
3527,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8533785 | [
"No",
"difference",
"in",
"the",
"parental",
"origin",
"of",
"susceptibility",
"HLA",
"class",
"II",
"haplotypes",
"among",
"Norwegian",
"patients",
"with",
"insulin-dependent",
"diabetes",
"mellitus."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | No difference in the parental origin of susceptibility HLA class II haplotypes among Norwegian patients with insulin-dependent diabetes mellitus. | [
2,
2239,
3175,
1922,
1920,
7213,
4853,
1927,
6461,
7225,
2921,
2890,
12149,
2706,
21190,
2132,
1956,
4122,
17,
3100,
4032,
9695,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
8651280 | [
"Autosomal",
"recessive",
"Wolfram",
"syndrome",
"associated",
"with",
"an",
"8.5-kb",
"mtDNA",
"single",
"deletion.",
"Wolfram",
"syndrome",
"(MIM",
"222300)",
"is",
"characterized",
"by",
"optic",
"atrophy,",
"diabetes",
"mellitus,",
"diabetes",
"insipidus,",
"neurosensory",
"hearing",
"loss,",
"urinary",
"tract",
"abnormalities,",
"and",
"neurological",
"dysfunction.",
"The",
"association",
"of",
"clinical",
"manifestations",
"in",
"tissues",
"and",
"organs",
"unrelated",
"functionally",
"or",
"embryologically",
"suggested",
"the",
"possibility",
"of",
"a",
"mitochondrial",
"implication",
"in",
"the",
"disease,",
"which",
"has",
"been",
"demonstrated",
"in",
"two",
"sporadic",
"cases.",
"Nonetheless,",
"familial",
"studies",
"suggested",
"an",
"autosomal",
"recessive",
"mode",
"of",
"transmission,",
"and",
"recent",
"data",
"demonstrated",
"linkage",
"with",
"markers",
"on",
"the",
"short",
"arm",
"of",
"human",
"chromosome",
"4.",
"The",
"patient",
"reported",
"here,",
"as",
"well",
"as",
"her",
"parents",
"and",
"unaffected",
"sister,",
"carried",
"a",
"heteroplasmic",
"8.5-kb",
"deletion",
"in",
"mtDNA.",
"The",
"deletion",
"accounted",
"for",
"23%",
"of",
"mitochondrial",
"genomes",
"in",
"lymphocytes",
"from",
"the",
"patient",
"and",
"approximately",
"5%",
"in",
"the",
"tissues",
"studied",
"from",
"members",
"of",
"her",
"family.",
"The",
"presence",
"of",
"the",
"deletion",
"in",
"the",
"patient",
"in",
"a",
"proportion",
"higher",
"than",
"in",
"her",
"unaffected",
"parents",
"suggests",
"a",
"putative",
"defect",
"in",
"a",
"nuclear",
"gene",
"that",
"acts",
"at",
"the",
"mitochondrial",
"level."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single deletion. Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract abnormalities, and neurological dysfunction. The association of clinical manifestations in tissues and organs unrelated functionally or embryologically suggested the possibility of a mitochondrial implication in the disease, which has been demonstrated in two sporadic cases. Nonetheless, familial studies suggested an autosomal recessive mode of transmission, and recent data demonstrated linkage with markers on the short arm of human chromosome 4. The patient reported here, as well as her parents and unaffected sister, carried a heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of mitochondrial genomes in lymphocytes from the patient and approximately 5% in the tissues studied from members of her family. The presence of the deletion in the patient in a proportion higher than in her unaffected parents suggests a putative defect in a nuclear gene that acts at the mitochondrial level. | [
2,
13027,
13992,
25254,
29085,
4741,
2458,
1956,
1925,
28,
18,
25,
17,
6633,
11183,
2957,
5541,
18,
25254,
29085,
4741,
12,
6571,
16903,
17450,
13,
1977,
4378,
2007,
10109,
10260,
16,
4032,
9695,
16,
4032,
2346,
2049,
22291,
16,
7318,
12680,
8512,
3257,
16,
7075,
6482,
6754,
16,
1930,
7605,
5273,
18,
1920,
3279,
1927,
2535,
10952,
1922,
3878,
1930,
7393,
10295,
9346,
2014,
9222,
22284,
2901,
3978,
1920,
5341,
1927,
43,
4596,
18058,
1922,
1920,
2573,
16,
2154,
2258,
2252,
3161,
1922,
2288,
13088,
2919,
18,
10850,
16,
11444,
2351,
3978,
1925,
13027,
13992,
5754,
1927,
5303,
16,
1930,
3505,
2230,
3161,
8611,
1956,
4432,
1990,
1920,
3662,
6011,
1927,
2616,
5597,
24,
18,
1920,
2774,
2568,
3410,
16,
1966,
2486,
1966,
3656,
5853,
1930,
10403,
14611,
16,
4371,
43,
19732,
15403,
1935,
28,
18,
25,
17,
6633,
5541,
1922,
11183,
18,
1920,
5541,
9448,
1958,
3020,
9,
1927,
4596,
7313,
1922,
7257,
2037,
1920,
2774,
1930,
3993,
25,
9,
1922,
1920,
3878,
3942,
2037,
4678,
1927,
3656,
3416,
18,
1920,
2990,
1927,
1920,
5541,
1922,
1920,
2774,
1922,
43,
4242,
2580,
2254,
1922,
3656,
10403,
5853,
4015,
43,
6770,
7374,
1922,
43,
4254,
2359,
1988,
8016,
2019,
1920,
4596,
2237,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
10841811 | [
"Segregation",
"analysis",
"of",
"esophageal",
"cancer",
"in",
"a",
"moderately",
"high-incidence",
"area",
"of",
"northern",
"China.",
"In",
"order",
"to",
"explore",
"the",
"mode",
"of",
"inheritance",
"of",
"esophageal",
"cancer",
"in",
"a",
"moderately",
"high-incidence",
"area",
"of",
"northern",
"China,",
"we",
"conducted",
"a",
"pedigree",
"survey",
"on",
"225",
"patients",
"affected",
"by",
"esophageal",
"cancer",
"in",
"Yangquan,",
"Shanxi",
"Province.",
"Segregation",
"analysis",
"was",
"performed",
"using",
"the",
"REGTL",
"program",
"of",
"S.A.G.E.",
"The",
"results",
"showed",
"that",
"Mendelian",
"autosomal",
"recessive",
"inheritance",
"of",
"a",
"major",
"gene",
"that",
"influences",
"susceptibility",
"to",
"esophageal",
"cancer",
"provided",
"the",
"best",
"fit",
"to",
"the",
"data.",
"In",
"the",
"best-fitting",
"recessive",
"model,",
"the",
"frequency",
"of",
"the",
"disease",
"allele",
"was.2039.",
"There",
"was",
"a",
"significant",
"sex",
"effect",
"on",
"susceptibility",
"to",
"the",
"disease.",
"The",
"maximum",
"cumulative",
"probability",
"of",
"esophageal",
"cancer",
"among",
"males",
"with",
"the",
"AA",
"genotype",
"was",
"100%,",
"but,",
"among",
"females,",
"it",
"was",
"63.5%.",
"The",
"mean",
"age",
"at",
"onset",
"for",
"both",
"men",
"and",
"women",
"was",
"62",
"years.",
"The",
"age-dependent",
"penetrances",
"for",
"males",
"with",
"the",
"AA",
"genotype",
"by",
"the",
"ages",
"of",
"60",
"and",
"80",
"years",
"were",
"41.6%",
"and",
"95.2%,",
"respectively,",
"whereas,",
"for",
"females,",
"they",
"were",
"26.4%",
"and",
"60.5%,",
"respectively.",
"Incorporating",
"environmental",
"risk",
"factors-such",
"as",
"cigarette",
"smoking,",
"pipe",
"smoking,",
"alcohol",
"drinking,",
"eating",
"hot",
"food,",
"and",
"eating",
"pickled",
"vegetables-into",
"the",
"models",
"did",
"not",
"provide",
"significant",
"improvement",
"of",
"the",
"fit",
"of",
"the",
"models",
"to",
"these",
"data.",
"The",
"results",
"suggest",
"a",
"major",
"locus",
"underlying",
"susceptibility",
"to",
"esophageal",
"cancer",
"with",
"sex-specific",
"penetrance."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Segregation analysis of esophageal cancer in a moderately high-incidence area of northern China. In order to explore the mode of inheritance of esophageal cancer in a moderately high-incidence area of northern China, we conducted a pedigree survey on 225 patients affected by esophageal cancer in Yangquan, Shanxi Province. Segregation analysis was performed using the REGTL program of S.A.G.E. The results showed that Mendelian autosomal recessive inheritance of a major gene that influences susceptibility to esophageal cancer provided the best fit to the data. In the best-fitting recessive model, the frequency of the disease allele was.2039. There was a significant sex effect on susceptibility to the disease. The maximum cumulative probability of esophageal cancer among males with the AA genotype was 100%, but, among females, it was 63.5%. The mean age at onset for both men and women was 62 years. The age-dependent penetrances for males with the AA genotype by the ages of 60 and 80 years were 41.6% and 95.2%, respectively, whereas, for females, they were 26.4% and 60.5%, respectively. Incorporating environmental risk factors-such as cigarette smoking, pipe smoking, alcohol drinking, eating hot food, and eating pickled vegetables-into the models did not provide significant improvement of the fit of the models to these data. The results suggest a major locus underlying susceptibility to esophageal cancer with sex-specific penetrance. | [
2,
12707,
2333,
1927,
10744,
2539,
1922,
43,
11224,
2149,
17,
4332,
3403,
1927,
9250,
5429,
18,
1922,
3238,
1942,
6414,
1920,
5754,
1927,
15762,
1927,
10744,
2539,
1922,
43,
11224,
2149,
17,
4332,
3403,
1927,
9250,
5429,
16,
2038,
3609,
43,
22336,
4711,
1990,
16056,
2132,
4218,
2007,
10744,
2539,
1922,
12662,
2048,
1928,
16,
11805,
18068,
11066,
18,
12707,
2333,
1982,
2593,
2193,
1920,
2147,
14598,
3688,
1927,
61,
18,
43,
18,
49,
18,
47,
18,
1920,
2274,
2594,
1988,
22702,
13027,
13992,
15762,
1927,
43,
3044,
2359,
1988,
8061,
6461,
1942,
10744,
2539,
3675,
1920,
4534,
3977,
1942,
1920,
2230,
18,
1922,
1920,
4534,
17,
9476,
13992,
2322,
16,
1920,
3528,
1927,
1920,
2573,
5465,
1982,
18,
16725,
1026,
18,
2276,
1982,
43,
2228,
3486,
2495,
1990,
6461,
1942,
1920,
2573,
18,
1920,
4419,
8274,
5485,
1927,
10744,
2539,
2706,
5129,
1956,
1920,
6440,
5619,
1982,
2813,
9,
16,
2308,
16,
2706,
5027,
16,
2176,
1982,
4968,
18,
25,
9,
18,
1920,
2667,
2632,
2019,
4727,
1958,
2321,
3925,
1930,
3089,
1982,
5374,
2739,
18,
1920,
2632,
17,
3100,
22035,
1036,
1958,
5129,
1956,
1920,
6440,
5619,
2007,
1920,
7684,
1927,
3276,
1930,
3729,
2739,
1985,
4353,
18,
26,
9,
1930,
3002,
18,
22,
9,
16,
2763,
16,
3417,
16,
1958,
5027,
16,
2611,
1985,
3179,
18,
24,
9,
1930,
3276,
18,
25,
9,
16,
2763,
18,
12553,
4813,
2565,
2790,
17,
2427,
1966,
10689,
5075,
16,
6556,
1021,
5075,
16,
4284,
7444,
16,
8979,
9529,
3959,
16,
1930,
8979,
13161,
2824,
14206,
17,
2460,
1920,
3130,
2811,
2084,
3394,
2228,
4990,
1927,
1920,
3977,
1927,
1920,
3130,
1942,
2144,
2230,
18,
1920,
2274,
3220,
43,
3044,
6730,
5030,
6461,
1942,
10744,
2539,
1956,
3486,
17,
2487,
22035,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
12145747 | [
"Tibial",
"muscular",
"dystrophy",
"is",
"a",
"titinopathy",
"caused",
"by",
"mutations",
"in",
"TTN",
",",
"the",
"gene",
"encoding",
"the",
"giant",
"skeletal-muscle",
"protein",
"titin.",
"Tibial",
"muscular",
"dystrophy",
"(TMD)",
"is",
"an",
"autosomal",
"dominant",
"late-onset",
"distal",
"myopathy",
"linked",
"to",
"chromosome",
"2q31.",
"The",
"linked",
"region",
"includes",
"the",
"giant",
"TTN",
" ",
"gene,",
"which",
"encodes",
"the",
"central",
"sarcomeric",
"protein,",
"titin.",
"We",
"have",
"previously",
"shown",
"a",
"secondary",
"calpain-3",
"defect",
"to",
"be",
"associated",
"with",
"TMD,",
"which",
"further",
"underscored",
"that",
"titin",
"is",
"the",
"candidate.",
"We",
"now",
"report",
"the",
"first",
"mutations",
"in",
"TTN",
" ",
"to",
"cause",
"a",
"human",
"skeletal-muscle",
"disease,",
"TMD.",
"In",
"Mex6,",
"the",
"last",
"exon",
"of",
"TTN",
",",
"a",
"unique",
"11-bp",
"deletion/insertion",
"mutation,",
"changing",
"four",
"amino",
"acid",
"residues,",
"completely",
"cosegregated",
"with",
"all",
"tested",
"81",
"Finnish",
"patients",
"with",
"TMD",
"in",
"12",
"unrelated",
"families.",
"The",
"mutation",
"was",
"not",
"found",
"in",
"216",
"Finnish",
"control",
"samples.",
"In",
"a",
"French",
"family",
"with",
"TMD,",
"a",
"Leu-->Pro",
"mutation",
"at",
"position",
"293,357",
" ",
"in",
"Mex6",
" ",
"was",
"discovered.",
"Mex6",
" ",
"is",
"adjacent",
"to",
"the",
"known",
"calpain-3",
"binding",
"site",
"Mex5",
" ",
"of",
"M-line",
"titin.",
"Immunohistochemical",
"analysis",
"using",
"two",
"exon-specific",
"antibodies",
"directed",
"to",
"the",
"M-line",
"region",
"of",
"titin",
"demonstrated",
"the",
"specific",
"loss",
"of",
"carboxy-terminal",
"titin",
"epitopes",
"in",
"the",
"TMD",
"muscle",
"samples",
"that",
"we",
"studied,",
"thus",
"implicating",
"a",
"functional",
"defect",
"of",
"the",
"M-line",
"titin",
"in",
"the",
"genesis",
"of",
"the",
"TMD",
"disease",
"phenotype."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
1,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Tibial muscular dystrophy is a titinopathy caused by mutations in TTN , the gene encoding the giant skeletal-muscle protein titin. Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN , a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype. | [
2,
13406,
12330,
19321,
1977,
43,
7090,
3522,
9112,
1012,
4189,
2007,
3527,
1922,
7382,
1022,
16,
1920,
2359,
5797,
1920,
15041,
7345,
17,
3760,
2213,
7090,
1921,
18,
13406,
12330,
19321,
12,
19958,
13,
1977,
1925,
13027,
6379,
5058,
17,
4727,
6583,
25017,
4624,
1942,
5597,
22,
1055,
6800,
18,
1920,
4624,
3031,
5921,
1920,
15041,
7382,
1022,
2359,
16,
2154,
9937,
1920,
4101,
8747,
8462,
2213,
16,
7090,
1921,
18,
2038,
2162,
3024,
2522,
43,
4067,
18811,
17,
23,
7374,
1942,
1998,
2458,
1956,
19958,
16,
2154,
2520,
23807,
1007,
1988,
7090,
1921,
1977,
1920,
6610,
18,
2038,
5195,
3809,
1920,
2561,
3527,
1922,
7382,
1022,
1942,
3936,
43,
2616,
7345,
17,
3760,
2573,
16,
19958,
18,
1922,
10114,
1016,
16,
1920,
4691,
7049,
1927,
7382,
1022,
16,
43,
5008,
2513,
17,
4149,
5541,
19,
7413,
3979,
16,
8546,
3006,
3835,
2687,
4248,
16,
5796,
4890,
6541,
3127,
1981,
1956,
2136,
3620,
6206,
24016,
2132,
1956,
19958,
1922,
2369,
10295,
5767,
18,
1920,
3979,
1982,
2084,
2435,
1922,
17663,
24016,
2285,
2785,
18,
1922,
43,
12941,
3416,
1956,
19958,
16,
43,
10632,
17,
17,
34,
1965,
3979,
2019,
3507,
9728,
16,
26099,
1922,
10114,
1016,
1982,
8117,
18,
10114,
1016,
1977,
6811,
1942,
1920,
3171,
18811,
17,
23,
2743,
3200,
10114,
1015,
1927,
55,
17,
2823,
7090,
1921,
18,
9885,
2333,
2193,
2288,
7049,
17,
2487,
3788,
6554,
1942,
1920,
55,
17,
2823,
3031,
1927,
7090,
1921,
3161,
1920,
2487,
3257,
1927,
15750,
17,
4262,
7090,
1921,
11427,
1922,
1920,
19958,
3760,
2785,
1988,
2038,
3942,
16,
2842,
21766,
43,
3183,
7374,
1927,
1920,
55,
17,
2823,
7090,
1921,
1922,
1920,
25309,
1927,
1920,
19958,
2573,
4629,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
1,
2,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20887961 | [
"Mutations",
"in",
"SCARF2",
" ",
"are",
"responsible",
"for",
"Van",
"Den",
"Ende-Gupta",
"syndrome.",
"Van",
"Den",
"Ende-Gupta",
"syndrome",
"(VDEGS)",
"is",
"an",
"extremely",
"rare",
"autosomal-recessive",
"disorder",
"characterized",
"by",
"distinctive",
"craniofacial",
"features,",
"which",
"include",
"blepharophimosis,",
"malar",
"and/or",
"maxillary",
"hypoplasia,",
"a",
"narrow",
"and",
"beaked",
"nose,",
"and",
"an",
"everted",
"lower",
"lip.",
"Other",
"features",
"are",
"arachnodactyly,",
"camptodactyly,",
"peculiar",
"skeletal",
"abnormalities,",
"and",
"normal",
"development",
"and",
"intelligence.",
"We",
"present",
"molecular",
"data",
"on",
"four",
"VDEGS",
"patients",
"from",
"three",
"consanguineous",
"Qatari",
"families",
"belonging",
"to",
"the",
"same",
"highly",
"inbred",
"Bedouin",
"tribe.",
"The",
"patients",
"were",
"genotyped",
"with",
"SNP",
"microarrays,",
"and",
"a",
"2.4",
"Mb",
"homozygous",
"region",
"was",
"found",
"on",
"chromosome",
"22q11",
"in",
"an",
"area",
"overlapping",
"the",
"DiGeorge",
"critical",
"region.",
"This",
"region",
"contained",
"44",
"genes,",
"including",
"SCARF2",
",",
"a",
"gene",
"that",
"is",
"expressed",
"during",
"development",
"in",
"a",
"number",
"of",
"mouse",
"tissues",
"relevant",
"to",
"the",
"symptoms",
"described",
"above.",
"Sanger",
"sequencing",
"identified",
"a",
"missense",
"change,",
"c.773G>A",
" ",
"(",
"p.C258Y",
"),",
"in",
"exon",
"4",
"in",
"the",
"two",
"closely",
"related",
"patients",
"and",
"a",
"2",
"bp",
"deletion",
"in",
"exon",
"8,",
"c.1328_1329delTG",
" ",
"(",
"p.V443DfsX83",
"),",
"in",
"two",
"unrelated",
"individuals.",
"In",
"parallel",
"with",
"the",
"candidate",
"gene",
"approach,",
"complete",
"exome",
"sequencing",
"was",
"used",
"to",
"confirm",
"that",
"SCARF2",
" ",
"was",
"the",
"gene",
"responsible",
"for",
"VDEGS.",
"SCARF2",
" ",
"contains",
"putative",
"epidermal",
"growth",
"factor-like",
"domains",
"in",
"its",
"extracellular",
"domain,",
"along",
"with",
"a",
"number",
"of",
"positively",
"charged",
"residues",
"in",
"its",
"intracellular",
"domain,",
"indicating",
"that",
"it",
"may",
"be",
"involved",
"in",
"intracellular",
"signaling.",
"However,",
"the",
"function",
"of",
"SCARF2",
" ",
"has",
"not",
"been",
"characterized,",
"and",
"this",
"study",
"reports",
"that",
"phenotypic",
"effects",
"can",
"be",
"associated",
"with",
"defects",
"in",
"the",
"scavenger",
"receptor",
"F",
"family",
"of",
"genes."
] | [
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Mutations in SCARF2 are responsible for Van Den Ende-Gupta syndrome. Van Den Ende-Gupta syndrome (VDEGS) is an extremely rare autosomal-recessive disorder characterized by distinctive craniofacial features, which include blepharophimosis, malar and/or maxillary hypoplasia, a narrow and beaked nose, and an everted lower lip. Other features are arachnodactyly, camptodactyly, peculiar skeletal abnormalities, and normal development and intelligence. We present molecular data on four VDEGS patients from three consanguineous Qatari families belonging to the same highly inbred Bedouin tribe. The patients were genotyped with SNP microarrays, and a 2.4 Mb homozygous region was found on chromosome 22q11 in an area overlapping the DiGeorge critical region. This region contained 44 genes, including SCARF2 , a gene that is expressed during development in a number of mouse tissues relevant to the symptoms described above. Sanger sequencing identified a missense change, c.773G>A ( p.C258Y ), in exon 4 in the two closely related patients and a 2 bp deletion in exon 8, c.1328_1329delTG ( p.V443DfsX83 ), in two unrelated individuals. In parallel with the candidate gene approach, complete exome sequencing was used to confirm that SCARF2 was the gene responsible for VDEGS. SCARF2 contains putative epidermal growth factor-like domains in its extracellular domain, along with a number of positively charged residues in its intracellular domain, indicating that it may be involved in intracellular signaling. However, the function of SCARF2 has not been characterized, and this study reports that phenotypic effects can be associated with defects in the scavenger receptor F family of genes. | [
2,
3527,
1922,
10218,
6680,
2032,
5061,
1958,
7409,
4533,
2482,
1021,
17,
3194,
25958,
4741,
18,
7409,
4533,
2482,
1021,
17,
3194,
25958,
4741,
12,
13411,
6541,
1036,
13,
1977,
1925,
8113,
5844,
13027,
17,
13992,
4770,
4378,
2007,
15308,
22530,
4075,
16,
2154,
3951,
6189,
4151,
2789,
1980,
2475,
16,
3054,
1933,
1930,
19,
2014,
15813,
25502,
16,
43,
8400,
1930,
1998,
19457,
16427,
16,
1930,
1925,
4264,
2013,
2826,
3178,
18,
2303,
4075,
2032,
15243,
11873,
3825,
2341,
24762,
16,
6225,
4575,
3825,
2341,
24762,
16,
22516,
7345,
6754,
16,
1930,
2791,
2740,
1930,
15206,
18,
2038,
2481,
3272,
2230,
1990,
3006,
13411,
6541,
1036,
2132,
2037,
2559,
29684,
19616,
2080,
23482,
3857,
3027,
5767,
10588,
1942,
1920,
2841,
3626,
19203,
7497,
4468,
1921,
14521,
1021,
18,
1920,
2132,
1985,
14401,
1956,
6821,
15913,
16,
1930,
43,
22,
18,
24,
5667,
9419,
3031,
1982,
2435,
1990,
5597,
2950,
23931,
1922,
1925,
3403,
8984,
1920,
4325,
1021,
1924,
2106,
4140,
3031,
18,
2052,
3031,
5543,
4044,
2628,
16,
2710,
10218,
6680,
16,
43,
2359,
1988,
1977,
3198,
2409,
2740,
1922,
43,
2529,
1927,
3321,
3878,
4494,
1942,
1920,
3601,
2910,
3538,
18,
16515,
4754,
2899,
43,
13519,
3185,
16,
45,
18,
5517,
24176,
34,
43,
12,
58,
18,
8453,
7532,
1012,
13,
16,
1922,
7049,
24,
1922,
1920,
2288,
6538,
2712,
2132,
1930,
43,
22,
4149,
5541,
1922,
7049,
28,
16,
45,
18,
11824,
1025,
41,
11824,
1026,
16878,
16960,
12,
58,
18,
19546,
7514,
12324,
1036,
1039,
11368,
13,
16,
1922,
2288,
10295,
3445,
18,
1922,
6110,
1956,
1920,
6610,
2359,
2998,
16,
4080,
16390,
4754,
1982,
2251,
1942,
4763,
1988,
10218,
6680,
1982,
1920,
2359,
5061,
1958,
13411,
6541,
1036,
18,
10218,
6680,
5461,
6770,
9844,
2905,
2991,
17,
3189,
4682,
1922,
2496,
5329,
3418,
16,
4231,
1956,
43,
2529,
1927,
6629,
9516,
4248,
1922,
2496,
4776,
3418,
16,
4168,
1988,
2176,
2278,
1998,
3286,
1922,
4776,
3197,
18,
2406,
16,
1920,
2347,
1927,
10218,
6680,
2258,
2084,
2252,
4378,
16,
1930,
2052,
2161,
4710,
1988,
8189,
2564,
2112,
1998,
2458,
1956,
6007,
1922,
1920,
21433,
3148,
48,
3416,
1927,
2628,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
19462467 | [
"Molecular",
"profiling",
"of",
"the",
"\"plexinome\"",
"in",
"melanoma",
"and",
"pancreatic",
"cancer.",
"Plexins",
"are",
"transmembrane",
"high-affinity",
"receptors",
"for",
"semaphorins,",
"regulating",
"cell",
"guidance,",
"motility,",
"and",
"invasion.",
"Functional",
"evidences",
"implicate",
"semaphorin",
"signals",
"in",
"cancer",
"progression",
"and",
"metastasis.",
"Yet,",
"it",
"is",
"largely",
"unknown",
"whether",
"plexin",
"genes",
"are",
"genetically",
"altered",
"in",
"human",
"tumors.",
"We",
"performed",
"a",
"comprehensive",
"gene",
"copy",
"analysis",
"and",
"mutational",
"profiling",
"of",
"all",
"nine",
"members",
"of",
"the",
"plexin",
"gene",
"family",
"(plexinome),",
"in",
"melanomas",
"and",
"pancreatic",
"ductal",
"adenocarcinomas",
"(PDACs),",
"which",
"are",
"characterized",
"by",
"high",
"metastatic",
"potential",
"and",
"poor",
"prognosis.",
"Gene",
"copy",
"analysis",
"detected",
"amplification",
"of",
"PLXNA4",
" ",
"in",
"melanomas,",
"whereas",
"copy",
"number",
"losses",
"of",
"multiple",
"plexin",
"genes",
"were",
"seen",
"in",
"PDACs.",
"Somatic",
"mutations",
"were",
"detected",
"in",
"PLXN",
"A",
"4,",
"PLXNB3",
",",
"and",
"PLXNC1",
";",
"providing",
"the",
"first",
"evidence",
"that",
"these",
"plexins",
"are",
"mutated",
"in",
"human",
"cancer.",
"Functional",
"assays",
"in",
"cellular",
"models",
"revealed",
"that",
"some",
"of",
"these",
"missense",
"mutations",
"result",
"in",
"loss",
"of",
"plexin",
"function.",
"For",
"instance,",
"c.1613G>A,",
"p.R538H",
" ",
"mutation",
"in",
"the",
"extracellular",
"domain",
"of",
"PLXNB3",
"c.1613G>A",
",",
"p.R538H",
"mutation",
"in",
"the",
"extracellular",
"domain",
"of",
"PLXNB3",
"prevented",
"binding",
"of",
"the",
"ligand",
"Sema5A.",
"Moreover,",
"although",
"PLXNA4",
"signaling",
"can",
"inhibit",
"tumor",
"cell",
"migration,",
"the",
"mutated",
"c.5206C>T,",
"p.H1736Y",
"c.5206C>T",
",",
"p.H1736Y",
"allele",
"had",
"lost",
"this",
"activity.",
"Our",
"study",
"is",
"the",
"first",
"systematic",
"analysis",
"of",
"the",
"\"plexinome\"",
"in",
"human",
"tumors,",
"and",
"indicates",
"that",
"multiple",
"mutated",
"plexins",
"may",
"be",
"involved",
"in",
"cancer",
"progression."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
1,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Molecular profiling of the "plexinome" in melanoma and pancreatic cancer. Plexins are transmembrane high-affinity receptors for semaphorins, regulating cell guidance, motility, and invasion. Functional evidences implicate semaphorin signals in cancer progression and metastasis. Yet, it is largely unknown whether plexin genes are genetically altered in human tumors. We performed a comprehensive gene copy analysis and mutational profiling of all nine members of the plexin gene family (plexinome), in melanomas and pancreatic ductal adenocarcinomas (PDACs), which are characterized by high metastatic potential and poor prognosis. Gene copy analysis detected amplification of PLXNA4 in melanomas, whereas copy number losses of multiple plexin genes were seen in PDACs. Somatic mutations were detected in PLXN A 4, PLXNB3 , and PLXNC1 ; providing the first evidence that these plexins are mutated in human cancer. Functional assays in cellular models revealed that some of these missense mutations result in loss of plexin function. For instance, c.1613G>A, p.R538H mutation in the extracellular domain of PLXNB3 c.1613G>A , p.R538H mutation in the extracellular domain of PLXNB3 prevented binding of the ligand Sema5A. Moreover, although PLXNA4 signaling can inhibit tumor cell migration, the mutated c.5206C>T, p.H1736Y c.5206C>T , p.H1736Y allele had lost this activity. Our study is the first systematic analysis of the "plexinome" in human tumors, and indicates that multiple mutated plexins may be involved in cancer progression. | [
2,
3272,
10156,
1927,
1920,
6,
11856,
3522,
3870,
6,
1922,
7033,
1930,
6356,
2539,
18,
11856,
2925,
2032,
9117,
2149,
17,
5173,
4086,
1958,
25799,
2102,
14258,
1036,
16,
6773,
2024,
9765,
16,
9254,
16,
1930,
6254,
18,
3183,
19827,
20781,
25799,
2102,
14258,
4771,
1922,
2539,
4380,
1930,
5967,
18,
4898,
16,
2176,
1977,
6318,
5435,
3053,
11856,
1921,
2628,
2032,
9517,
5520,
1922,
2616,
3861,
18,
2038,
2593,
43,
6911,
2359,
6983,
2333,
1930,
13736,
10156,
1927,
2136,
6360,
4678,
1927,
1920,
11856,
1921,
2359,
3416,
12,
11856,
3522,
3870,
13,
16,
1922,
20154,
1930,
6356,
15154,
19960,
12,
16812,
1036,
13,
16,
2154,
2032,
4378,
2007,
2149,
6476,
2889,
1930,
3930,
6573,
18,
2359,
6983,
2333,
3330,
6584,
1927,
2123,
1039,
2175,
1006,
1922,
20154,
16,
3417,
6983,
2529,
11783,
1927,
3137,
11856,
1921,
2628,
1985,
3945,
1922,
16812,
1036,
18,
8548,
3527,
1985,
3330,
1922,
2123,
1039,
1022,
43,
24,
16,
2123,
1039,
17046,
1010,
16,
1930,
2123,
1039,
15895,
1009,
31,
5453,
1920,
2561,
3095,
1988,
2144,
11856,
2925,
2032,
8336,
1922,
2616,
2539,
18,
3183,
4614,
1922,
3689,
3130,
3404,
1988,
2673,
1927,
2144,
13519,
3527,
3211,
1922,
3257,
1927,
11856,
1921,
2347,
18,
1958,
7303,
16,
45,
18,
15729,
24176,
34,
43,
16,
58,
18,
21316,
4745,
1023,
3979,
1922,
1920,
5329,
3418,
1927,
2123,
1039,
17046,
1010,
45,
18,
15729,
24176,
34,
43,
16,
58,
18,
21316,
4745,
1023,
3979,
1922,
1920,
5329,
3418,
1927,
2123,
1039,
17046,
1010,
8715,
2743,
1927,
1920,
5207,
25799,
9422,
18,
3950,
16,
2876,
2123,
1039,
2175,
1006,
3197,
2112,
2875,
2798,
2024,
5049,
16,
1920,
8336,
45,
18,
20386,
20316,
34,
62,
16,
58,
18,
9169,
8966,
1016,
1012,
45,
18,
20386,
20316,
34,
62,
16,
58,
18,
9169,
8966,
1016,
1012,
5465,
2430,
7621,
2052,
2455,
18,
2342,
2161,
1977,
1920,
2561,
5614,
2333,
1927,
1920,
6,
11856,
3522,
3870,
6,
1922,
2616,
3861,
16,
1930,
4538,
1988,
3137,
8336,
11856,
2925,
2278,
1998,
3286,
1922,
2539,
4380,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
1,
2,
2,
2,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
1,
2,
2,
2,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
3,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20127982 | [
"Disruption",
"of",
"OTC",
"promoter-enhancer",
"interaction",
"in",
"a",
"patient",
"with",
"symptoms",
"of",
"ornithine",
"carbamoyltransferase",
"deficiency.",
"In",
"a",
"female",
"patient",
"with",
"signs",
"of",
"ornithine",
"carbamoyltransferase",
"deficiency",
"(OTCD),",
"the",
"only",
"variation",
"found",
"was",
"a",
"heterozygous",
"single",
"nucleotide",
"substitution",
"c.-366A>G",
".",
"Determination",
"of",
"transcription",
"start",
"sites",
"of",
"human",
"OTC",
"95,",
"119",
"and",
"169",
"bp",
"upstream",
"of",
"the",
"initiation",
"codon",
"located",
"the",
"variation",
"upstream",
"of",
"the",
"5'-untranslated",
"region.",
"We",
"predicted",
"the",
"human",
"promoter",
"and",
"enhancer",
"elements",
"from",
"homology",
"with",
"rat",
"and",
"mouse,",
"performed",
"function",
"analysis",
"of",
"both",
"regulatory",
"regions",
"and",
"assessed",
"the",
"impact",
"of",
"the",
"promoter",
"variation",
"in",
"functional",
"studies",
"using",
"dual",
"luciferase",
"reporter",
"assay.",
"Our",
"data",
"indicate",
"that:",
"(i)",
"Full",
"transcriptional",
"activity",
"of",
"human",
"OTC",
"promoter",
"depends",
"on",
"an",
"upstream",
"enhancer,",
"as",
"do",
"the",
"rodent",
"promoters.",
"(ii)",
"The",
"promoter",
"variation",
"c.-366A>G",
"OTC",
" ",
"promoter-enhancer",
"interaction",
"in",
"a",
"patient",
"with",
"symptoms",
"of",
"ornithine",
"carbamoyltransferase",
"deficiency.",
"In",
"a",
"female",
"patient",
"with",
"signs",
"of",
"ornithine",
"carbamoyltransferase",
"deficiency",
"(OTCD),",
"the",
"only",
"variation",
"found",
"was",
"a",
"heterozygous",
"single",
"nucleotide",
"substitution",
"c.-366A>G.",
"Determination",
"of",
"transcription",
"start",
"sites",
"of",
"human",
"OTC",
"95,",
"119",
"and",
"169",
"bp",
"upstream",
"of",
"the",
"initiation",
"codon",
"located",
"the",
"variation",
"upstream",
"of",
"the",
"5'-untranslated",
"region.",
"We",
"predicted",
"the",
"human",
"promoter",
"and",
"enhancer",
"elements",
"from",
"homology",
"with",
"rat",
"and",
"mouse,",
"performed",
"function",
"analysis",
"of",
"both",
"regulatory",
"regions",
"and",
"assessed",
"the",
"impact",
"of",
"the",
"promoter",
"variation",
"in",
"functional",
"studies",
"using",
"dual",
"luciferase",
"reporter",
"assay.",
"Our",
"data",
"indicate",
"that:",
"(i)",
"Full",
"transcriptional",
"activity",
"of",
"human",
"OTC",
"OTC",
" ",
"95,",
"119",
"and",
"169",
"bp",
"upstream",
"of",
"the",
"initiation",
"codon",
"located",
"the",
"variation",
"upstream",
"of",
"the",
"5'-untranslated",
"region.",
"We",
"predicted",
"the",
"human",
"promoter",
"and",
"enhancer",
"elements",
"from",
"homology",
"with",
"rat",
"and",
"mouse,",
"performed",
"function",
"analysis",
"of",
"both",
"regulatory",
"regions",
"and",
"assessed",
"the",
"impact",
"of",
"the",
"promoter",
"variation",
"in",
"functional",
"studies",
"using",
"dual",
"luciferase",
"reporter",
"assay.",
"Our",
"data",
"indicate",
"that:",
"(i)",
"Full",
"transcriptional",
"activity",
"of",
"human",
"OTC",
"promoter",
"depends",
"on",
"an",
"upstream",
"enhancer,",
"as",
"do",
"the",
"rodent",
"promoters.",
"(ii)",
"The",
"promoter",
"variation",
"c.-366A>G",
"does",
"not",
"affect",
"the",
"function",
"of",
"the",
"promoter",
"alone",
"but",
"it",
"disrupts",
"the",
"interaction",
"of",
"the",
"promoter",
"with",
"the",
"enhancer.",
"(iii)",
"The",
"promoter-enhancer",
"interaction",
"contributes",
"to",
"tissue",
"specific",
"expression",
"of",
"OTC",
" ",
"in",
"the",
"liver.",
"We",
"conclude",
"that",
"mutations",
"in",
"the",
"regulatory",
"regions",
"of",
"OTC",
" ",
"can",
"lead",
"to",
"OTCD",
"and",
"should",
"be",
"included",
"in",
"genetic",
"testing."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Disruption of OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency. In a female patient with signs of ornithine carbamoyltransferase deficiency (OTCD), the only variation found was a heterozygous single nucleotide substitution c.-366A>G . Determination of transcription start sites of human OTC 95, 119 and 169 bp upstream of the initiation codon located the variation upstream of the 5'-untranslated region. We predicted the human promoter and enhancer elements from homology with rat and mouse, performed function analysis of both regulatory regions and assessed the impact of the promoter variation in functional studies using dual luciferase reporter assay. Our data indicate that: (i) Full transcriptional activity of human OTC promoter depends on an upstream enhancer, as do the rodent promoters. (ii) The promoter variation c.-366A>G OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency. In a female patient with signs of ornithine carbamoyltransferase deficiency (OTCD), the only variation found was a heterozygous single nucleotide substitution c.-366A>G. Determination of transcription start sites of human OTC 95, 119 and 169 bp upstream of the initiation codon located the variation upstream of the 5'-untranslated region. We predicted the human promoter and enhancer elements from homology with rat and mouse, performed function analysis of both regulatory regions and assessed the impact of the promoter variation in functional studies using dual luciferase reporter assay. Our data indicate that: (i) Full transcriptional activity of human OTC OTC 95, 119 and 169 bp upstream of the initiation codon located the variation upstream of the 5'-untranslated region. We predicted the human promoter and enhancer elements from homology with rat and mouse, performed function analysis of both regulatory regions and assessed the impact of the promoter variation in functional studies using dual luciferase reporter assay. Our data indicate that: (i) Full transcriptional activity of human OTC promoter depends on an upstream enhancer, as do the rodent promoters. (ii) The promoter variation c.-366A>G does not affect the function of the promoter alone but it disrupts the interaction of the promoter with the enhancer. (iii) The promoter-enhancer interaction contributes to tissue specific expression of OTC in the liver. We conclude that mutations in the regulatory regions of OTC can lead to OTCD and should be included in genetic testing. | [
2,
7561,
1927,
7608,
1030,
4465,
17,
10992,
2835,
1922,
43,
2774,
1956,
3601,
1927,
26918,
17742,
10921,
9961,
6179,
18,
1922,
43,
4232,
2774,
1956,
6879,
1927,
26918,
17742,
10921,
9961,
6179,
12,
7608,
9547,
13,
16,
1920,
2444,
4516,
2435,
1982,
43,
9589,
2957,
5489,
6636,
45,
18,
17,
26725,
1019,
34,
49,
18,
7063,
1927,
3213,
6413,
3402,
1927,
2616,
7608,
1030,
3002,
16,
11022,
1930,
15237,
4149,
7671,
1927,
1920,
6035,
8905,
4810,
1920,
4516,
7671,
1927,
1920,
25,
11,
17,
19522,
3031,
18,
2038,
4396,
1920,
2616,
4465,
1930,
10992,
5362,
2037,
9039,
1956,
3067,
1930,
3321,
16,
2593,
2347,
2333,
1927,
2321,
4948,
3451,
1930,
3683,
1920,
3829,
1927,
1920,
4465,
4516,
1922,
3183,
2351,
2193,
7064,
7362,
6734,
3381,
18,
2342,
2230,
3579,
1988,
30,
12,
51,
13,
4125,
5224,
2455,
1927,
2616,
7608,
1030,
4465,
7315,
1990,
1925,
7671,
10992,
16,
1966,
2608,
1920,
11880,
9026,
18,
12,
2890,
13,
1920,
4465,
4516,
45,
18,
17,
26725,
1019,
34,
49,
7608,
1030,
4465,
17,
10992,
2835,
1922,
43,
2774,
1956,
3601,
1927,
26918,
17742,
10921,
9961,
6179,
18,
1922,
43,
4232,
2774,
1956,
6879,
1927,
26918,
17742,
10921,
9961,
6179,
12,
7608,
9547,
13,
16,
1920,
2444,
4516,
2435,
1982,
43,
9589,
2957,
5489,
6636,
45,
18,
17,
26725,
1019,
34,
49,
18,
7063,
1927,
3213,
6413,
3402,
1927,
2616,
7608,
1030,
3002,
16,
11022,
1930,
15237,
4149,
7671,
1927,
1920,
6035,
8905,
4810,
1920,
4516,
7671,
1927,
1920,
25,
11,
17,
19522,
3031,
18,
2038,
4396,
1920,
2616,
4465,
1930,
10992,
5362,
2037,
9039,
1956,
3067,
1930,
3321,
16,
2593,
2347,
2333,
1927,
2321,
4948,
3451,
1930,
3683,
1920,
3829,
1927,
1920,
4465,
4516,
1922,
3183,
2351,
2193,
7064,
7362,
6734,
3381,
18,
2342,
2230,
3579,
1988,
30,
12,
51,
13,
4125,
5224,
2455,
1927,
2616,
7608,
1030,
7608,
1030,
3002,
16,
11022,
1930,
15237,
4149,
7671,
1927,
1920,
6035,
8905,
4810,
1920,
4516,
7671,
1927,
1920,
25,
11,
17,
19522,
3031,
18,
2038,
4396,
1920,
2616,
4465,
1930,
10992,
5362,
2037,
9039,
1956,
3067,
1930,
3321,
16,
2593,
2347,
2333,
1927,
2321,
4948,
3451,
1930,
3683,
1920,
3829,
1927,
1920,
4465,
4516,
1922,
3183,
2351,
2193,
7064,
7362,
6734,
3381,
18,
2342,
2230,
3579,
1988,
30,
12,
51,
13,
4125,
5224,
2455,
1927,
2616,
7608,
1030,
4465,
7315,
1990,
1925,
7671,
10992,
16,
1966,
2608,
1920,
11880,
9026,
18,
12,
2890,
13,
1920,
4465,
4516,
45,
18,
17,
26725,
1019,
34,
49,
3731,
2084,
4081,
1920,
2347,
1927,
1920,
4465,
4298,
2308,
2176,
18605,
1920,
2835,
1927,
1920,
4465,
1956,
1920,
10992,
18,
12,
4337,
13,
1920,
4465,
17,
10992,
2835,
7624,
1942,
2960,
2487,
2294,
1927,
7608,
1030,
1922,
1920,
3568,
18,
2038,
7676,
1988,
3527,
1922,
1920,
4948,
3451,
1927,
7608,
1030,
2112,
2949,
1942,
7608,
9547,
1930,
3066,
1998,
3063,
1922,
3299,
4213,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20537301 | [
"A",
"definitive",
"haplotype",
"map",
"as",
"determined",
"by",
"genotyping",
"duplicated",
"haploid",
"genomes",
"finds",
"a",
"predominant",
"haplotype",
"preference",
"at",
"copy-number",
"variation",
"events.",
"The",
"majority",
"of",
"complete",
"hydatidiform",
"moles",
"(CHMs)",
"harbor",
"duplicated",
"haploid",
"genomes",
"that",
"originate",
"from",
"sperm.",
"This",
"makes",
"CHMs",
"more",
"advantageous",
"than",
"conventional",
"diploid",
"cells",
"for",
"determining",
"haplotypes",
"of",
"SNPs",
"and",
"copy-number",
"variations",
"(CNVs),",
"because",
"all",
"of",
"the",
"genetic",
"variants",
"in",
"a",
"CHM",
"genome",
"are",
"homozygous.",
"Here",
"we",
"report",
"SNP",
"and",
"CNV",
"haplotype",
"structures",
"determined",
"by",
"analysis",
"of",
"100",
"CHMs",
"from",
"Japanese",
"subjects",
"via",
"high-density",
"DNA",
"arrays.",
"The",
"obtained",
"haplotype",
"map",
"should",
"be",
"useful",
"as",
"a",
"reference",
"for",
"the",
"haplotype",
"structure",
"of",
"Asian",
"populations.",
"We",
"resolved",
"common",
"CNV",
"regions",
"(merged",
"CNV",
"segments",
"across",
"the",
"examined",
"samples)",
"into",
"CNV",
"events",
"(clusters",
"of",
"CNV",
"segments)",
"on",
"the",
"basis",
"of",
"mutual",
"overlap",
"and",
"found",
"that",
"the",
"haplotype",
"backgrounds",
"of",
"different",
"CNV",
"events",
"within",
"the",
"same",
"CNV",
"region",
"were",
"predominantly",
"similar,",
"perhaps",
"because",
"of",
"inherent",
"structural",
"instability."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | A definitive haplotype map as determined by genotyping duplicated haploid genomes finds a predominant haplotype preference at copy-number variation events. The majority of complete hydatidiform moles (CHMs) harbor duplicated haploid genomes that originate from sperm. This makes CHMs more advantageous than conventional diploid cells for determining haplotypes of SNPs and copy-number variations (CNVs), because all of the genetic variants in a CHM genome are homozygous. Here we report SNP and CNV haplotype structures determined by analysis of 100 CHMs from Japanese subjects via high-density DNA arrays. The obtained haplotype map should be useful as a reference for the haplotype structure of Asian populations. We resolved common CNV regions (merged CNV segments across the examined samples) into CNV events (clusters of CNV segments) on the basis of mutual overlap and found that the haplotype backgrounds of different CNV events within the same CNV region were predominantly similar, perhaps because of inherent structural instability. | [
2,
43,
12072,
10949,
4446,
1966,
3180,
2007,
10667,
19479,
20812,
7313,
25153,
43,
6136,
10949,
8308,
2019,
6983,
17,
2529,
4516,
3916,
18,
1920,
4827,
1927,
4080,
2993,
8525,
6154,
22372,
1036,
12,
2016,
2800,
13,
14355,
19479,
20812,
7313,
1988,
16786,
2037,
6283,
18,
2052,
7645,
2016,
2800,
2253,
16761,
2254,
5552,
16613,
2094,
1958,
7426,
12149,
1927,
6084,
1930,
6983,
17,
2529,
6740,
12,
20393,
13,
16,
2882,
2136,
1927,
1920,
3299,
4936,
1922,
43,
2016,
1035,
3843,
2032,
9419,
18,
3410,
2038,
3809,
6821,
1930,
15590,
10949,
4061,
3180,
2007,
2333,
1927,
2813,
2016,
2800,
2037,
10405,
3297,
3454,
2149,
17,
3824,
2678,
10517,
18,
1920,
2926,
10949,
4446,
3066,
1998,
4707,
1966,
43,
4386,
1958,
1920,
10949,
3170,
1927,
9686,
4098,
18,
2038,
8397,
3059,
15590,
3451,
12,
15780,
15590,
7492,
3436,
1920,
3572,
2785,
13,
2460,
15590,
3916,
12,
5859,
1927,
15590,
7492,
13,
1990,
1920,
4859,
1927,
14445,
7713,
1930,
2435,
1988,
1920,
10949,
15650,
1927,
2413,
15590,
3916,
2651,
1920,
2841,
15590,
3031,
1985,
7700,
2551,
16,
8011,
2882,
1927,
11590,
4346,
9557,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
7537150 | [
"Identification",
"of",
"six",
"mutations",
"(",
"R31L",
",",
"441delA",
",",
"681delC",
",",
"1461ins4",
",",
"W1089R",
",",
"E1104X",
")",
"in",
"the",
"cystic",
"fibrosis",
"transmembrane",
"conductance",
"regulator",
"(",
"CFTR",
")",
"gene.",
"Six",
"new",
"mutations",
"have",
"been",
"identified",
"in",
"the",
"CFTR",
"gene.",
"These",
"mutations,",
"representing",
"three",
"different",
"categories--missense",
"(",
"R31L",
",",
"W1098R",
"),",
"nonsense",
"(",
"E1104X",
"),",
"and",
"frameshift",
"(",
"441delA",
",",
"681delC",
",",
"1461ins4",
")--are",
"located",
"in",
"exons",
"2,",
"4,",
"5,",
"9,",
"and",
"17b",
"of",
"the",
"gene",
"and",
"presumed",
"to",
"cause",
"cystic",
"fibrosis",
"(CF)",
"in",
"patients.",
"All",
"these",
"mutations",
"are",
"probably",
"rare",
"in",
"the",
"population,",
"as",
"no",
"additional",
"examples",
"were",
"found",
"for",
"any",
"of",
"them",
"in",
"a",
"cohort",
"of",
"545",
"CF",
"patients.",
"Our",
"study",
"also",
"revealed",
"a",
"benign",
"sequence",
"variation",
"(",
"3499",
"+",
"45T-->C",
"cystic",
"fibrosis",
"transmembrane",
"conductance",
"regulator",
" ",
"(CFTR)",
"gene.",
"Six",
"new",
"mutations",
"have",
"been",
"identified",
"in",
"the",
"CFTR",
"gene.",
"These",
"mutations,",
"representing",
"three",
"different",
"categories--missense",
"(R31L,",
"W1098R),",
"nonsense",
"(E1104X),",
"and",
"frameshift",
"(441delA,",
"681delC,",
"1461ins4)--are",
"located",
"in",
"exons",
"2,",
"4,",
"5,",
"9,",
"and",
"17b",
"of",
"the",
"gene",
"and",
"presumed",
"to",
"cause",
"cystic",
"fibrosis",
"(CF)",
"in",
"patients.",
"All",
"these",
"mutations",
"are",
"probably",
"rare",
"in",
"the",
"population,",
"as",
"no",
"additional",
"examples",
"were",
"found",
"for",
"any",
"of",
"them",
"in",
"a",
"cohort",
"of",
"545",
"CF",
"patients.",
"Our",
"study",
"also",
"revealed",
"a",
"benign",
"sequence",
"variation",
"(3499",
"+",
"45T-->C)",
"in",
"intron",
"17b."
] | [
0,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
0,
3,
0,
0,
0,
3,
0,
0,
0,
0,
3,
0,
3,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Identification of six mutations ( R31L , 441delA , 681delC , 1461ins4 , W1089R , E1104X ) in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. Six new mutations have been identified in the CFTR gene. These mutations, representing three different categories--missense ( R31L , W1098R ), nonsense ( E1104X ), and frameshift ( 441delA , 681delC , 1461ins4 )--are located in exons 2, 4, 5, 9, and 17b of the gene and presumed to cause cystic fibrosis (CF) in patients. All these mutations are probably rare in the population, as no additional examples were found for any of them in a cohort of 545 CF patients. Our study also revealed a benign sequence variation ( 3499 + 45T-->C cystic fibrosis transmembrane conductance regulator (CFTR) gene. Six new mutations have been identified in the CFTR gene. These mutations, representing three different categories--missense (R31L, W1098R), nonsense (E1104X), and frameshift (441delA, 681delC, 1461ins4)--are located in exons 2, 4, 5, 9, and 17b of the gene and presumed to cause cystic fibrosis (CF) in patients. All these mutations are probably rare in the population, as no additional examples were found for any of them in a cohort of 545 CF patients. Our study also revealed a benign sequence variation (3499 + 45T-->C) in intron 17b. | [
2,
4824,
1927,
3798,
3527,
12,
19217,
23101,
16,
29904,
16878,
1019,
16,
5117,
18737,
1938,
1030,
16,
13402,
1009,
2925,
1006,
16,
28651,
13895,
1026,
1005,
16,
26564,
14743,
1039,
13,
1922,
1920,
11656,
6769,
9117,
11977,
7888,
12,
13533,
13,
2359,
18,
3798,
2814,
3527,
2162,
2252,
2899,
1922,
1920,
13533,
2359,
18,
2144,
3527,
16,
7479,
2559,
2413,
6118,
17,
17,
13519,
12,
19217,
23101,
16,
28651,
13192,
1025,
1005,
13,
16,
19605,
12,
26564,
14743,
1039,
13,
16,
1930,
21848,
12,
29904,
16878,
1019,
16,
5117,
18737,
1938,
1030,
16,
13402,
1009,
2925,
1006,
13,
17,
17,
2032,
4810,
1922,
10419,
22,
16,
24,
16,
25,
16,
29,
16,
1930,
2752,
1014,
1927,
1920,
2359,
1930,
15326,
1942,
3936,
11656,
6769,
12,
4920,
13,
1922,
2132,
18,
2136,
2144,
3527,
2032,
6226,
5844,
1922,
1920,
2973,
16,
1966,
2239,
3281,
7604,
1985,
2435,
1958,
2967,
1927,
3581,
1922,
43,
4382,
1927,
4584,
1015,
4920,
2132,
18,
2342,
2161,
2222,
3404,
43,
8867,
3244,
4516,
12,
26925,
1026,
15,
3607,
1031,
17,
17,
34,
45,
11656,
6769,
9117,
11977,
7888,
12,
13533,
13,
2359,
18,
3798,
2814,
3527,
2162,
2252,
2899,
1922,
1920,
13533,
2359,
18,
2144,
3527,
16,
7479,
2559,
2413,
6118,
17,
17,
13519,
12,
19217,
23101,
16,
28651,
13192,
1025,
1005,
13,
16,
19605,
12,
26564,
14743,
1039,
13,
16,
1930,
21848,
12,
29904,
16878,
1019,
16,
5117,
18737,
1938,
1030,
16,
13402,
1009,
2925,
1006,
13,
17,
17,
2032,
4810,
1922,
10419,
22,
16,
24,
16,
25,
16,
29,
16,
1930,
2752,
1014,
1927,
1920,
2359,
1930,
15326,
1942,
3936,
11656,
6769,
12,
4920,
13,
1922,
2132,
18,
2136,
2144,
3527,
2032,
6226,
5844,
1922,
1920,
2973,
16,
1966,
2239,
3281,
7604,
1985,
2435,
1958,
2967,
1927,
3581,
1922,
43,
4382,
1927,
4584,
1015,
4920,
2132,
18,
2342,
2161,
2222,
3404,
43,
8867,
3244,
4516,
12,
26925,
1026,
15,
3607,
1031,
17,
17,
34,
45,
13,
1922,
10444,
2752,
1014,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
3,
4,
0,
3,
4,
4,
0,
3,
4,
4,
4,
0,
3,
4,
4,
4,
0,
3,
4,
4,
4,
0,
3,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
0,
3,
4,
4,
4,
0,
0,
0,
0,
3,
4,
4,
0,
0,
0,
0,
0,
3,
4,
4,
0,
3,
4,
4,
4,
0,
3,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
1,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
20137772 | [
"Autosomal-recessive",
"hypophosphatemic",
"rickets",
"is",
"associated",
"with",
"an",
"inactivation",
"mutation",
"in",
"the",
"ENPP1",
" ",
"gene.",
"Human",
"disorders",
"of",
"phosphate",
"(Pi)",
"handling",
"and",
"hypophosphatemic",
"rickets",
"have",
"been",
"shown",
"to",
"result",
"from",
"mutations",
"in",
"PHEX",
",",
"FGF23",
",",
"and",
"DMP1",
",",
"presenting",
"as",
"X-linked",
"recessive,",
"autosomal-dominant,",
"and",
"autosomal-recessive",
"patterns,",
"respectively.",
"We",
"present",
"the",
"identification",
"of",
"an",
"inactivating",
"mutation",
"in",
"the",
"ecto-nucleotide",
"pyrophosphatase/phosphodiesterase",
"1",
"(",
"ENPP1",
"pyrophosphatase/phosphodiesterase",
"1",
" ",
"(ENPP1)",
"gene",
"causing",
"autosomal-recessive",
"hypophosphatemic",
"rickets",
"(ARHR)",
"with",
"phosphaturia",
"by",
"positional",
"cloning.",
"ENPP1",
" ",
"generates",
"inorganic",
"pyrophosphate",
"(PPi),",
"an",
"essential",
"physiologic",
"inhibitor",
"of",
"calcification,",
"and",
"previously",
"described",
"inactivating",
"mutations",
"in",
"this",
"gene",
"were",
"shown",
"to",
"cause",
"aberrant",
"ectopic",
"calcification",
"disorders,",
"whereas",
"no",
"aberrant",
"calcifications",
"were",
"present",
"in",
"our",
"patients.",
"Our",
"surprising",
"result",
"suggests",
"a",
"different",
"pathway",
"involved",
"in",
"the",
"generation",
"of",
"ARHR",
"and",
"possible",
"additional",
"functions",
"for",
"ENPP1",
"."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0
] | Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX , FGF23 , and DMP1 , presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1 . | [
2,
13027,
17,
13992,
26497,
10647,
3508,
2722,
2057,
4913,
19507,
3441,
1977,
2458,
1956,
1925,
8005,
3979,
1922,
1920,
2066,
9434,
1009,
2359,
18,
2616,
4414,
1927,
5413,
12,
4269,
13,
12361,
1930,
26497,
10647,
3508,
2722,
2057,
4913,
19507,
3441,
2162,
2252,
2522,
1942,
3211,
2037,
3527,
1922,
10422,
1039,
16,
26635,
16,
1930,
29487,
1009,
16,
8326,
1966,
66,
17,
4624,
13992,
16,
13027,
17,
6379,
16,
1930,
13027,
17,
13992,
4147,
16,
2763,
18,
2038,
2481,
1920,
4824,
1927,
1925,
20862,
3979,
1922,
1920,
7495,
1037,
17,
5489,
20661,
2609,
7234,
19,
24821,
21,
12,
2066,
9434,
1009,
20661,
2609,
7234,
19,
24821,
21,
12,
2066,
9434,
1009,
13,
2359,
7538,
13027,
17,
13992,
26497,
10647,
3508,
2722,
2057,
4913,
19507,
3441,
12,
25710,
1005,
13,
1956,
2766,
1926,
8754,
2007,
20172,
11501,
18,
2066,
9434,
1009,
12399,
13849,
24937,
12,
12481,
13,
16,
1925,
4415,
13900,
4106,
1927,
14640,
16,
1930,
3024,
2910,
20862,
3527,
1922,
2052,
2359,
1985,
2522,
1942,
3936,
9801,
11092,
14640,
4414,
16,
3417,
2239,
9801,
28711,
1985,
2481,
1922,
2342,
2132,
18,
2342,
7620,
3211,
4015,
43,
2413,
3374,
3286,
1922,
1920,
4841,
1927,
25710,
1005,
1930,
3216,
3281,
4088,
1958,
2066,
9434,
1009,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
1,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
-100
] |
17847001 | [
"Copy-number",
"variations",
"measured",
"by",
"single-nucleotide-polymorphism",
"oligonucleotide",
"arrays",
"in",
"patients",
"with",
"mental",
"retardation.",
"Whole-genome",
"analysis",
"using",
"high-density",
"single-nucleotide-polymorphism",
"oligonucleotide",
"arrays",
"allows",
"identification",
"of",
"microdeletions,",
"microduplications,",
"and",
"uniparental",
"disomies.",
"We",
"studied",
"67",
"children",
"with",
"unexplained",
"mental",
"retardation",
"with",
"normal",
"karyotypes,",
"as",
"assessed",
"by",
"G-banded",
"chromosome",
"analyses.",
"Their",
"DNAs",
"were",
"analyzed",
"with",
"Affymetrix",
"100K",
"arrays.",
"We",
"detected",
"11",
"copy-number",
"variations",
"that",
"most",
"likely",
"are",
"causative",
"of",
"mental",
"retardation,",
"because",
"they",
"either",
"arose",
"de",
"novo",
"(9",
"cases)",
"and/or",
"overlapped",
"with",
"known",
"microdeletions",
"(2",
"cases).",
"The",
"eight",
"deletions",
"and",
"three",
"duplications",
"varied",
"in",
"size",
"from",
"200",
"kb",
"to",
"7.5",
"Mb.",
"Of",
"the",
"11",
"copy-number",
"variations,",
"5",
"were",
"flanked",
"by",
"low-copy",
"repeats.",
"Two",
"of",
"those,",
"on",
"chromosomes",
"15q25.2",
"and",
"Xp22.31,",
"have",
"not",
"been",
"described",
"before",
"and",
"have",
"a",
"high",
"probability",
"of",
"being",
"causative",
"of",
"new",
"deletion",
"and",
"duplication",
"syndromes,",
"respectively.",
"In",
"one",
"patient,",
"we",
"found",
"a",
"deletion",
"affecting",
"only",
"a",
"single",
"gene,",
"MBD5",
",",
"which",
"codes",
"for",
"the",
"methyl-CpG-binding",
"domain",
"protein",
"5",
".",
"In",
"addition",
"to",
"the",
"67",
"children,",
"we",
"investigated",
"4",
"mentally",
"retarded",
"children",
"with",
"apparent",
"balanced",
"translocations",
"and",
"detected",
"four",
"deletions",
"at",
"breakpoint",
"regions",
"ranging",
"in",
"size",
"from",
"1.1",
"to",
"14",
"Mb."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
1,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Whole-genome analysis using high-density single-nucleotide-polymorphism oligonucleotide arrays allows identification of microdeletions, microduplications, and uniparental disomies. We studied 67 children with unexplained mental retardation with normal karyotypes, as assessed by G-banded chromosome analyses. Their DNAs were analyzed with Affymetrix 100K arrays. We detected 11 copy-number variations that most likely are causative of mental retardation, because they either arose de novo (9 cases) and/or overlapped with known microdeletions (2 cases). The eight deletions and three duplications varied in size from 200 kb to 7.5 Mb. Of the 11 copy-number variations, 5 were flanked by low-copy repeats. Two of those, on chromosomes 15q25.2 and Xp22.31, have not been described before and have a high probability of being causative of new deletion and duplication syndromes, respectively. In one patient, we found a deletion affecting only a single gene, MBD5 , which codes for the methyl-CpG-binding domain protein 5 . In addition to the 67 children, we investigated 4 mentally retarded children with apparent balanced translocations and detected four deletions at breakpoint regions ranging in size from 1.1 to 14 Mb. | [
2,
6983,
17,
2529,
6740,
3045,
2007,
2957,
17,
5489,
17,
8218,
12346,
10517,
1922,
2132,
1956,
5018,
16342,
18,
4292,
17,
3843,
2333,
2193,
2149,
17,
3824,
2957,
17,
5489,
17,
8218,
12346,
10517,
5731,
4824,
1927,
14320,
5484,
2443,
16,
14320,
3481,
3742,
2082,
16,
1930,
15943,
2768,
4905,
1923,
2054,
1947,
2062,
18,
2038,
3942,
4838,
3069,
1956,
21109,
5018,
16342,
1956,
2791,
21954,
1036,
16,
1966,
3683,
2007,
49,
17,
5472,
1919,
5597,
3247,
18,
2310,
20207,
1985,
3265,
1956,
15677,
2813,
1040,
10517,
18,
2038,
3330,
2513,
6983,
17,
2529,
6740,
1988,
2501,
3205,
2032,
13939,
1927,
5018,
16342,
16,
2882,
2611,
3108,
19521,
2028,
9441,
12,
29,
2919,
13,
1930,
19,
2014,
17389,
1956,
3171,
14320,
5484,
2443,
12,
22,
2919,
13,
18,
1920,
5066,
10550,
1930,
2559,
20559,
6760,
1922,
3081,
2037,
2191,
6633,
1942,
27,
18,
25,
5667,
18,
1927,
1920,
2513,
6983,
17,
2529,
6740,
16,
25,
1985,
20185,
2007,
2330,
17,
6983,
9569,
18,
2288,
1927,
2690,
16,
1990,
8597,
2461,
23470,
1015,
18,
22,
1930,
15930,
4460,
18,
3470,
16,
2162,
2084,
2252,
2910,
3119,
1930,
2162,
43,
2149,
5485,
1927,
3301,
13939,
1927,
2814,
5541,
1930,
12630,
12688,
16,
2763,
18,
1922,
2340,
2774,
16,
2038,
2435,
43,
5541,
7359,
2444,
43,
2957,
2359,
16,
5667,
1007,
1015,
16,
2154,
9756,
1958,
1920,
4963,
17,
9383,
17,
2743,
3418,
2213,
25,
18,
1922,
2459,
1942,
1920,
4838,
3069,
16,
2038,
3845,
24,
29294,
27603,
3069,
1956,
6273,
12045,
22436,
1930,
3330,
3006,
10550,
2019,
24698,
3451,
6485,
1922,
3081,
2037,
21,
18,
21,
1942,
2607,
5667,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
2,
0,
0,
0,
0,
0,
1,
2,
2,
2,
2,
2,
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |
17879353 | [
"Multiple",
"endocrine",
"neoplasia",
"type",
"1",
"(MEN1):",
"analysis",
"of",
"1336",
"mutations",
"reported",
"in",
"the",
"first",
"decade",
"following",
"identification",
"of",
"the",
"gene.",
"Multiple",
"endocrine",
"neoplasia",
"type",
"1",
"(MEN1)",
"is",
"an",
"autosomal",
"dominant",
"disorder",
"characterized",
"by",
"the",
"occurrence",
"of",
"tumors",
"of",
"the",
"parathyroids,",
"pancreas,",
"and",
"anterior",
"pituitary.",
"The",
"MEN1",
" ",
"gene,",
"which",
"was",
"identified",
"in",
"1997,",
"consists",
"of",
"10",
"exons",
"that",
"encode",
"a",
"610-amino",
"acid",
"protein",
"referred",
"to",
"as",
"menin",
".",
"Menin",
" ",
"is",
"predominantly",
"a",
"nuclear",
"protein",
"that",
"has",
"roles",
"in",
"transcriptional",
"regulation,",
"genome",
"stability,",
"cell",
"division,",
"and",
"proliferation.",
"Germline",
"mutations",
"usually",
"result",
"in",
"MEN1",
"or",
"occasionally",
"in",
"an",
"allelic",
"variant",
"referred",
"to",
"as",
"familial",
"isolated",
"hyperparathyroidism",
"(FIHP).",
"MEN1",
"tumors",
"frequently",
"have",
"loss",
"of",
"heterozygosity",
"(LOH)",
"of",
"the",
"MEN1",
" ",
"locus,",
"which",
"is",
"consistent",
"with",
"a",
"tumor",
"suppressor",
"role",
"of",
"MEN1",
".",
"Furthermore,",
"somatic",
"abnormalities",
"of",
"MEN1",
" ",
"have",
"been",
"reported",
"in",
"MEN1",
"and",
"non-MEN1",
"endocrine",
"tumors.",
"The",
"clinical",
"aspects",
"and",
"molecular",
"genetics",
"of",
"MEN1",
" ",
"are",
"reviewed",
"together",
"with",
"the",
"reported",
"1,336",
"mutations.",
"The",
"majority",
"(>70%)",
"of",
"these",
"mutations",
"are",
"predicted",
"to",
"lead",
"to",
"truncated",
"forms",
"of",
"menin.",
"The",
"mutations",
"are",
"scattered",
"throughout",
"the>9-kb",
"genomic",
"sequence",
"of",
"the",
"MEN1",
" ",
"gene.",
"Four,",
"which",
"consist",
"of",
"c.249_252delGTCT",
" ",
"(deletion",
"at",
"codons",
"83-84),",
"c.1546_1547insC",
" ",
"(insertion",
"at",
"codon",
"516),",
"c.1378C>T",
" ",
"(",
"Arg460Ter",
"),",
"and",
"c.628_631delACAG",
" ",
"(deletion",
"at",
"codons",
"210-211)",
"have",
"been",
"reported",
"to",
"occur",
"frequently",
"in",
"4.5%,",
"2.7%,",
"2.6%,",
"and",
"2.5%",
"of",
"families,",
"respectively.",
"However,",
"a",
"comparison",
"of",
"the",
"clinical",
"features",
"in",
"patients",
"and",
"their",
"families",
"with",
"the",
"same",
"mutations",
"reveals",
"an",
"absence",
"of",
"phenotype-genotype",
"correlations.",
"The",
"majority",
"of",
"MEN1",
" ",
"mutations",
"are",
"likely",
"to",
"disrupt",
"the",
"interactions",
"of",
"menin",
"with",
"other",
"proteins",
"and",
"thereby",
"alter",
"critical",
"events",
"in",
"cell",
"cycle",
"regulation",
"and",
"proliferation."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
3,
0,
0,
0,
0,
0,
3,
0,
0,
3,
0,
0,
3,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610-amino acid protein referred to as menin . Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1 . Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T ( Arg460Ter ), and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. | [
2,
3137,
10749,
17773,
2601,
21,
12,
3925,
1009,
13,
30,
2333,
1927,
12147,
1016,
3527,
2568,
1922,
1920,
2561,
10468,
2894,
4824,
1927,
1920,
2359,
18,
3137,
10749,
17773,
2601,
21,
12,
3925,
1009,
13,
1977,
1925,
13027,
6379,
4770,
4378,
2007,
1920,
6564,
1927,
3861,
1927,
1920,
17152,
1036,
16,
10936,
16,
1930,
5477,
10621,
18,
1920,
3925,
1009,
2359,
16,
2154,
1982,
2899,
1922,
6000,
16,
7543,
1927,
2119,
10419,
1988,
11107,
43,
26762,
17,
3835,
2687,
2213,
6656,
1942,
1966,
3925,
1921,
18,
3925,
1921,
1977,
7700,
43,
4254,
2213,
1988,
2258,
5456,
1922,
5224,
3640,
16,
3843,
5057,
16,
2024,
8451,
16,
1930,
4031,
18,
12237,
3527,
5394,
3211,
1922,
3925,
1009,
2014,
14647,
1922,
1925,
13045,
6031,
6656,
1942,
1966,
11444,
3937,
30247,
12,
14856,
15870,
13,
18,
3925,
1009,
3861,
5467,
2162,
3257,
1927,
18896,
12,
19716,
13,
1927,
1920,
3925,
1009,
6730,
16,
2154,
1977,
3499,
1956,
43,
2798,
9241,
2770,
1927,
3925,
1009,
18,
3677,
16,
8548,
6754,
1927,
3925,
1009,
2162,
2252,
2568,
1922,
3925,
1009,
1930,
2447,
17,
3925,
1009,
10749,
3861,
18,
1920,
2535,
6082,
1930,
3272,
10072,
1927,
3925,
1009,
2032,
5487,
4084,
1956,
1920,
2568,
21,
16,
25423,
3527,
18,
1920,
4827,
12,
34,
3895,
9,
13,
1927,
2144,
3527,
2032,
4396,
1942,
2949,
1942,
9530,
4952,
1927,
3925,
1921,
18,
1920,
3527,
2032,
15522,
5264,
1920,
34,
29,
17,
6633,
4935,
3244,
1927,
1920,
3925,
1009,
2359,
18,
3006,
16,
2154,
3149,
1927,
45,
18,
21218,
41,
21979,
16878,
17215,
1031,
12,
5541,
2019,
14500,
5893,
17,
5686,
13,
16,
45,
18,
14396,
1016,
41,
14396,
1027,
2925,
1030,
12,
7413,
2019,
8905,
4892,
1016,
13,
16,
45,
18,
11960,
1025,
1030,
34,
62,
12,
4582,
7772,
1008,
1967,
13,
16,
1930,
45,
18,
5374,
1025,
41,
4968,
18737,
15208,
3375,
1029,
12,
5541,
2019,
14500,
12348,
17,
18196,
13,
2162,
2252,
2568,
1942,
4704,
5467,
1922,
24,
18,
25,
9,
16,
22,
18,
27,
9,
16,
22,
18,
26,
9,
16,
1930,
22,
18,
25,
9,
1927,
5767,
16,
2763,
18,
2406,
16,
43,
3723,
1927,
1920,
2535,
4075,
1922,
2132,
1930,
2310,
5767,
1956,
1920,
2841,
3527,
9179,
1925,
3905,
1927,
4629,
17,
5619,
6100,
18,
1920,
4827,
1927,
3925,
1009,
3527,
2032,
3205,
1942,
12512,
1920,
3719,
1927,
3925,
1921,
1956,
2303,
2697,
1930,
6113,
4238,
4140,
3916,
1922,
2024,
4048,
3640,
1930,
4031,
18,
3
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | [
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1
] | [
-100,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
0,
3,
4,
4,
4,
0,
0,
0,
3,
4,
4,
4,
4,
4,
4,
4,
4,
4,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
1,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
-100
] |