id
stringlengths 1
3
| document_id
stringlengths 7
8
| passages
list | entities
list | events
list | coreferences
list | relations
list |
|---|---|---|---|---|---|---|
100 | 1539591 | [
{
"id": "1539591__text",
"type": "abstract",
"text": [
"A truncated dystrophin lacking the C-terminal domains is localized at the muscle membrane. A Duchenne muscular dystrophy patient who displayed near-normal dystrophin staining at the sarcolemma with N-terminal, but not with C-terminal, anti-dystrophin monoclonal antibodies was found to have a frameshift deletion of exons 42 and 43. This deletion introduces an early termination codon, and a 225-kD protein was detected by western blotting with N-terminal antibodies only. The results suggest that an N-terminal truncated dystrophin fragment encoded by exon 1-41 is able to associate with the muscle cell membrane. The current idea that the C-terminal domains of dystrophin are important or essential for its integration with the sarcolemma may have to be reexamined in the light of these observations.\n"
],
"offsets": [
[
0,
803
]
]
}
] | [] | [] | [] | [] |
101 | 1346075 | [
{
"id": "1346075__text",
"type": "abstract",
"text": [
"Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21. We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.\n"
],
"offsets": [
[
0,
1568
]
]
}
] | [] | [] | [] | [] |
102 | 1609807 | [
{
"id": "1609807__text",
"type": "abstract",
"text": [
"Anticipation legitimized: unstable DNA to the rescue.\n"
],
"offsets": [
[
0,
54
]
]
}
] | [] | [] | [] | [] |
103 | 1415265 | [
{
"id": "1415265__text",
"type": "abstract",
"text": [
"Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.\n"
],
"offsets": [
[
0,
954
]
]
}
] | [] | [] | [] | [] |
104 | 1329505 | [
{
"id": "1329505__text",
"type": "abstract",
"text": [
"SSCP and segregation analysis of the human type X collagen gene (COL10A1) in heritable forms of chondrodysplasia. Type X collagen is a homotrimeric, short chain, nonfibrillar collagen that is expressed exclusively by hypertrophic chondrocytes at the sites of endochondral ossification. The distribution and pattern of expression of the type X collagen gene (COL10A1) suggests that mutations altering the structure and synthesis of the protein may be responsible for causing heritable forms of chondrodysplasia. We investigated whether mutations within the human COL10A1 gene were responsible for causing the disorders achondroplasia, hypochondroplasia, pseudoachondroplasia, and thanatophoric dysplasia, by analyzing the coding regions of the gene by using PCR and the single-stranded conformational polymorphism technique. By this approach, seven sequence changes were identified within and flanking the coding regions of the gene of the affected persons. We demonstrated that six of these sequence changes were not responsible for causing these forms of chondrodysplasia but were polymorphic in nature. The sequence changes were used to demonstrate discordant segregation between the COL10A1 locus and achondroplasia and pseudoachondroplasia, in nuclear families. This lack of segregation suggests that mutations within or near the COL10A1 locus are not responsible for these disorders. The seventh sequence change resulted in a valine-to-methionine substitution in the carboxyl-terminal domain of the molecule and was identified in only two hypochondroplasic individuals from a single family. Segregation analysis in this family was inconclusive, and the significance of this substitution remains uncertain.\n"
],
"offsets": [
[
0,
1711
]
]
}
] | [
{
"id": "1329505_T1",
"type": "Gene",
"text": [
"COL10A1"
],
"offsets": [
[
65,
72
]
],
"normalized": []
},
{
"id": "1329505_T2",
"type": "Gene",
"text": [
"COL10A1"
],
"offsets": [
[
358,
365
]
],
"normalized": []
},
{
"id": "1329505_T3",
"type": "Gene",
"text": [
"type X collagen"
],
"offsets": [
[
336,
351
]
],
"normalized": []
},
{
"id": "1329505_T4",
"type": "Gene",
"text": [
"human type X collagen"
],
"offsets": [
[
37,
58
]
],
"normalized": []
},
{
"id": "1329505_T5",
"type": "Gene",
"text": [
"COL10A1"
],
"offsets": [
[
562,
569
]
],
"normalized": []
},
{
"id": "1329505_T6",
"type": "Gene",
"text": [
"COL10A1"
],
"offsets": [
[
1186,
1193
]
],
"normalized": []
},
{
"id": "1329505_T7",
"type": "Gene",
"text": [
"COL10A1"
],
"offsets": [
[
1334,
1341
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1329505_R1",
"type": "Equals",
"arg1_id": "1329505_T3",
"arg2_id": "1329505_T2",
"normalized": []
},
{
"id": "1329505_R2",
"type": "Equals",
"arg1_id": "1329505_T4",
"arg2_id": "1329505_T1",
"normalized": []
}
] |
105 | 1609795 | [
{
"id": "1609795__text",
"type": "abstract",
"text": [
"The human gene encoding acetylcholinesterase is located on the long arm of chromosome 7. Acetylcholinesterase (AChE) is a secreted enzyme essential for regulating cholinergic neurotransmission at neuronal and neuromuscular synapses. In view of the altered expression of AChE in some central neurological and neuromuscular disorders with a probable genetic basis, we have identified the chromosomal location of the gene encoding AChE. Chromosomal in situ suppression hybridization analysis revealed a single gene to be at 7q22, a result which was confirmed by PCR analysis of genomic DNA from a human/hamster somatic cell hybrid containing a single human chromosome 7. The AChE gene thus maps to the same region in which frequent nonrandom chromosome 7 deletions occur in leukemias of myeloid cell precursors known to express the enzyme during normal differentiation.\n"
],
"offsets": [
[
0,
867
]
]
}
] | [
{
"id": "1609795_T1",
"type": "Gene",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
24,
44
]
],
"normalized": []
},
{
"id": "1609795_T2",
"type": "Gene",
"text": [
"Acetylcholinesterase"
],
"offsets": [
[
89,
109
]
],
"normalized": []
},
{
"id": "1609795_T3",
"type": "Gene",
"text": [
"AChE"
],
"offsets": [
[
111,
115
]
],
"normalized": []
},
{
"id": "1609795_T4",
"type": "Gene",
"text": [
"AChE"
],
"offsets": [
[
270,
274
]
],
"normalized": []
},
{
"id": "1609795_T5",
"type": "Gene",
"text": [
"AChE"
],
"offsets": [
[
428,
432
]
],
"normalized": []
},
{
"id": "1609795_T6",
"type": "Gene",
"text": [
"AChE"
],
"offsets": [
[
672,
676
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1609795_R1",
"type": "Equals",
"arg1_id": "1609795_T2",
"arg2_id": "1609795_T3",
"normalized": []
}
] |
106 | 1357966 | [
{
"id": "1357966__text",
"type": "abstract",
"text": [
"Linkage disequilibrium among RFLPs at the insulin-receptor locus despite intervening Alu repeat sequences. Multiple mutations of the insulin receptor (INSR) gene have been identified in individuals with extreme insulin resistance. These mutations have included recombination events between Alu repeat units in the tyrosine kinase-encoding beta-chain region of the gene. To evaluate the influence of Alu and dinucleotide repetitive sequences on recombination events within the insulin receptor gene, I examined the degree of linkage disequilibrium between RFLP pairs spanning the gene. I established 228 independent haplotypes for seven RFLPs (two each for PstI, RsaI, and SstI and one for MspI and 172 independent haplotypes which included an additional RFLP with BglII) from 19 pedigrees. These RFLPs span > 130 kb of this gene, and my colleagues and I previously demonstrated that multiple Alu sequences separate RFLP pairs. Observed haplotype frequencies deviated significantly from those predicted. Pairwise analysis of RFLP showed high levels of linkage disequilibrium among RFLP in the beta-chain region of the insulin receptor, but not between alpha-chain RFLPs and those of the beta-chain. Disequilibrium was present among beta-chain RFLPs, despite separation by one or more Alu repeat sequences. The very strong linkage disequilibrium which was present in sizable regions of the INSR gene despite the presence of both Alu and microsatellite repeats suggested that these regions do not have a major impact on recombinations at this locus.\n"
],
"offsets": [
[
0,
1547
]
]
}
] | [
{
"id": "1357966_T1",
"type": "Gene",
"text": [
"INSR"
],
"offsets": [
[
151,
155
]
],
"normalized": []
},
{
"id": "1357966_T2",
"type": "Gene",
"text": [
"insulin receptor"
],
"offsets": [
[
133,
149
]
],
"normalized": []
},
{
"id": "1357966_T4",
"type": "Gene",
"text": [
"PstI,"
],
"offsets": [
[
656,
661
]
],
"normalized": []
},
{
"id": "1357966_T5",
"type": "Gene",
"text": [
"RsaI,"
],
"offsets": [
[
662,
667
]
],
"normalized": []
},
{
"id": "1357966_T6",
"type": "Gene",
"text": [
"SstI"
],
"offsets": [
[
672,
676
]
],
"normalized": []
},
{
"id": "1357966_T7",
"type": "Gene",
"text": [
"MspI"
],
"offsets": [
[
689,
693
]
],
"normalized": []
},
{
"id": "1357966_T8",
"type": "Gene",
"text": [
"BglII"
],
"offsets": [
[
764,
769
]
],
"normalized": []
},
{
"id": "1357966_T9",
"type": "Gene",
"text": [
"INSR"
],
"offsets": [
[
1388,
1392
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1357966_R1",
"type": "Equals",
"arg1_id": "1357966_T2",
"arg2_id": "1357966_T1",
"normalized": []
}
] |
107 | 1729895 | [
{
"id": "1729895__text",
"type": "abstract",
"text": [
"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 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.\n"
],
"offsets": [
[
0,
1330
]
]
}
] | [
{
"id": "1729895_T1",
"type": "Gene",
"text": [
"HLA-DR"
],
"offsets": [
[
53,
59
]
],
"normalized": []
},
{
"id": "1729895_T2",
"type": "Gene",
"text": [
"HLA"
],
"offsets": [
[
94,
97
]
],
"normalized": []
},
{
"id": "1729895_T3",
"type": "Gene",
"text": [
"HLA"
],
"offsets": [
[
275,
278
]
],
"normalized": []
},
{
"id": "1729895_T4",
"type": "Gene",
"text": [
"HLA-DR"
],
"offsets": [
[
293,
299
]
],
"normalized": []
},
{
"id": "1729895_T5",
"type": "Gene",
"text": [
"HLA-B"
],
"offsets": [
[
887,
892
]
],
"normalized": []
},
{
"id": "1729895_T6",
"type": "Gene",
"text": [
"HLA-DR"
],
"offsets": [
[
738,
744
]
],
"normalized": []
},
{
"id": "1729895_T7",
"type": "Gene",
"text": [
"HLA-DR"
],
"offsets": [
[
648,
654
]
],
"normalized": []
},
{
"id": "1729895_T8",
"type": "Gene",
"text": [
"HLA-DR"
],
"offsets": [
[
1230,
1236
]
],
"normalized": []
},
{
"id": "1729895_T9",
"type": "Gene",
"text": [
"HLA-B"
],
"offsets": [
[
1323,
1328
]
],
"normalized": []
},
{
"id": "1729895_T10",
"type": "Gene",
"text": [
"HLA"
],
"offsets": [
[
1134,
1137
]
],
"normalized": []
},
{
"id": "1729895_T11",
"type": "Gene",
"text": [
"HLA-B"
],
"offsets": [
[
930,
935
]
],
"normalized": []
}
] | [] | [] | [] |
108 | 1463020 | [
{
"id": "1463020__text",
"type": "abstract",
"text": [
"Importance sampling. I. Computing multimodel p values in linkage analysis. In linkage analysis, when the lod score is maximized over multiple genetic models, standard asymptotic approximation of the significance level does not apply. Monte Carlo methods can be used to estimate the p value, but procedures currently used are extremely inefficient. We propose a Monte Carlo procedure based on the concept of importance sampling, which can be thousands of times more efficient than current procedures. With a reasonable amount of computing time, extremely accurate estimates of the p values can be obtained. Both theoretical results and an example of maturity-onset diabetes of the young (MODY) are presented to illustrate the efficiency performance of our method. Relations between single-model and multimodel p values are explored. The new procedure is also used to investigate the performance of asymptotic approximations in a single model situation.\n"
],
"offsets": [
[
0,
952
]
]
}
] | [] | [] | [] | [] |
109 | 1317992 | [
{
"id": "1317992__text",
"type": "abstract",
"text": [
"Increased genetic instability of the common fragile site at 3p14 after integration of exogenous DNA. We determined previously that the selectable marker pSV2neo is preferentially inserted into chromosomal fragile sites in human x hamster hybrid cells in the presence of an agent (aphidicolin) that induces fragile-site expression. In contrast, cells transfected without fragile-site induction showed an essentially random integration pattern. To determine whether the integration of marker DNA at fragile sites affects the frequency of fragile-site expression, the parental hybrid and three transfectants (two with pSV2neo integrated at the fragile site at 3p14.2 [FRA3B] and specific hamster fragile sites [chromosome 1, bands q26-31, or mar2, bands q11-13] and one with pSV2neo integrated at sites that are not fragile sites) were treated with aphidicolin. After 24 h the two cell lines with plasmid integration at FRA3B showed structural rearrangements at that site; these rearrangements accounted for 43%-67% of the total deletions and translocations observed. Structural rearrangements were not observed in the parental cell line. After 5 d aphidicolin treatment, the observed excess in frequency of structural rearrangements at FRA3B in the cell lines with pSV2neo integration at 3p14 over that in the two lines without FRA3B integration was less dramatic, but nonetheless significant. Fluorescent in situ hybridization (FISH) analysis of these cells, using a biotin-labeled pSV2neo probe, showed results consistent with the gross rearrangements detected cytogenetically in the lines with FRA3B integration; however, the pSV2neo sequences were frequently deleted concomitantly with translocations.(ABSTRACT TRUNCATED AT 250 WORDS)\n"
],
"offsets": [
[
0,
1737
]
]
}
] | [
{
"id": "1317992_T1",
"type": "Gene",
"text": [
"FRA3B"
],
"offsets": [
[
917,
922
]
],
"normalized": []
},
{
"id": "1317992_T2",
"type": "Gene",
"text": [
"FRA3B"
],
"offsets": [
[
1326,
1331
]
],
"normalized": []
},
{
"id": "1317992_T3",
"type": "Gene",
"text": [
"FRA3B"
],
"offsets": [
[
1595,
1600
]
],
"normalized": []
},
{
"id": "1317992_T4",
"type": "Gene",
"text": [
"FRA3B"
],
"offsets": [
[
665,
670
]
],
"normalized": []
},
{
"id": "1317992_T5",
"type": "Gene",
"text": [
"FRA3B"
],
"offsets": [
[
1234,
1239
]
],
"normalized": []
}
] | [] | [] | [] |
110 | 1346482 | [
{
"id": "1346482__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1460
]
]
}
] | [] | [] | [] | [] |
111 | 1373934 | [
{
"id": "1373934__text",
"type": "abstract",
"text": [
"Identification of a nonframeshift 84-bp deletion in exon 13 of the cystic fibrosis gene. Cystic fibrosis (CF) is the most frequent autosomal recessive inherited disorder in Caucasian populations. The disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We have identified an 84-bp deletion in exon 13 of the CFTR gene, detected by DNA amplification and direct sequencing of 500 bp of the 5' end of exon 13. The deletion was in the maternal allele of a CF patient bearing the delta F508 deletion in the father's allele. The same 84-bp deletion could also be detected in the patient's mother. The deletion spanned from a four-A cluster in positions 1949-1952 to another four-A cluster in positions 2032-2035, including 84 bp which correspond to codons 607-634 (1949del84). The reported mutation would result in the loss of 28 amino acid residues of the R domain of the CFTR protein.\n"
],
"offsets": [
[
0,
918
]
]
}
] | [
{
"id": "1373934_T1",
"type": "Gene",
"text": [
"cystic fibrosis"
],
"offsets": [
[
67,
82
]
],
"normalized": []
},
{
"id": "1373934_T2",
"type": "Gene",
"text": [
"CF transmembrane conductance regulator"
],
"offsets": [
[
238,
276
]
],
"normalized": []
},
{
"id": "1373934_T3",
"type": "Gene",
"text": [
"CFTR"
],
"offsets": [
[
278,
282
]
],
"normalized": []
},
{
"id": "1373934_T4",
"type": "Gene",
"text": [
"CFTR"
],
"offsets": [
[
345,
349
]
],
"normalized": []
},
{
"id": "1373934_T5",
"type": "SNP",
"text": [
"1949del84"
],
"offsets": [
[
796,
805
]
],
"normalized": []
},
{
"id": "1373934_T6",
"type": "Gene",
"text": [
"CFTR"
],
"offsets": [
[
904,
908
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1373934_R1",
"type": "Equals",
"arg1_id": "1373934_T2",
"arg2_id": "1373934_T3",
"normalized": []
},
{
"id": "1373934_R2",
"type": "AssociatedTo",
"arg1_id": "1373934_T5",
"arg2_id": "1373934_T4",
"normalized": []
}
] |
112 | 1347972 | [
{
"id": "1347972__text",
"type": "abstract",
"text": [
"Identification of heterogeneous PrP gene deletions in controls by detection of allele-specific heteroduplexes (DASH)\n"
],
"offsets": [
[
0,
117
]
]
}
] | [
{
"id": "1347972_T1",
"type": "Gene",
"text": [
"PrP"
],
"offsets": [
[
32,
35
]
],
"normalized": []
}
] | [] | [] | [] |
113 | 1570829 | [
{
"id": "1570829__text",
"type": "abstract",
"text": [
"Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. The human Y chromosome encodes a testis-determining factor (TDF) which is responsible for initiating male sex determination. Recently a region of the Y chromosome (SRY) was identified as part of the TDF gene. We have identified a three-generation family (N) in which all XY individuals have a single base-pair substitution resulting in a conservative amino acid change in the conserved domain of the SRY open reading frame. Three individuals are XY sex-reversed females, and two are XY males. Several models are proposed to explain association between a sequence variant in SRY and two sex phenotypes.\n"
],
"offsets": [
[
0,
707
]
]
}
] | [
{
"id": "1570829_T1",
"type": "Gene",
"text": [
"TDF"
],
"offsets": [
[
165,
168
]
],
"normalized": []
},
{
"id": "1570829_T2",
"type": "Gene",
"text": [
"testis-determining factor"
],
"offsets": [
[
138,
163
]
],
"normalized": []
},
{
"id": "1570829_T3",
"type": "Gene",
"text": [
"SRY"
],
"offsets": [
[
269,
272
]
],
"normalized": []
},
{
"id": "1570829_T4",
"type": "Gene",
"text": [
"TDF"
],
"offsets": [
[
304,
307
]
],
"normalized": []
},
{
"id": "1570829_T5",
"type": "Gene",
"text": [
"SRY"
],
"offsets": [
[
505,
508
]
],
"normalized": []
},
{
"id": "1570829_T6",
"type": "Gene",
"text": [
"SRY"
],
"offsets": [
[
679,
682
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1570829_R1",
"type": "Equals",
"arg1_id": "1570829_T2",
"arg2_id": "1570829_T1",
"normalized": []
}
] |
114 | 1598916 | [
{
"id": "1598916__text",
"type": "abstract",
"text": [
"Uniparental disomy 15 resulting from \"correction\" of an initial trisomy 15.\n"
],
"offsets": [
[
0,
76
]
]
}
] | [] | [] | [] | [] |
115 | 1415242 | [
{
"id": "1415242__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
599
]
]
}
] | [] | [] | [] | [] |
116 | 1598907 | [
{
"id": "1598907__text",
"type": "abstract",
"text": [
"A missense mutation (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 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.\n"
],
"offsets": [
[
0,
976
]
]
}
] | [
{
"id": "1598907_T1",
"type": "Gene",
"text": [
"lipoprotein lipase"
],
"offsets": [
[
52,
70
]
],
"normalized": []
},
{
"id": "1598907_T2",
"type": "SNP",
"text": [
"Trp86----Arg"
],
"offsets": [
[
21,
33
]
],
"normalized": []
},
{
"id": "1598907_T3",
"type": "Gene",
"text": [
"lipoprotein lipase"
],
"offsets": [
[
205,
223
]
],
"normalized": []
},
{
"id": "1598907_T4",
"type": "Gene",
"text": [
"LPL"
],
"offsets": [
[
225,
228
]
],
"normalized": []
},
{
"id": "1598907_T5",
"type": "Gene",
"text": [
"LPL"
],
"offsets": [
[
311,
314
]
],
"normalized": []
},
{
"id": "1598907_T6",
"type": "SNP",
"text": [
"Trp86----Arg"
],
"offsets": [
[
431,
443
]
],
"normalized": []
},
{
"id": "1598907_T7",
"type": "SNP",
"text": [
"T----C transition for codon 86 (TGG) at nucleotide 511"
],
"offsets": [
[
360,
414
]
],
"normalized": []
},
{
"id": "1598907_T8",
"type": "SNP",
"text": [
"C----T transition at nucleotide 571"
],
"offsets": [
[
464,
499
]
],
"normalized": []
},
{
"id": "1598907_T9",
"type": "SNP",
"text": [
"Gln106----Stop"
],
"offsets": [
[
555,
569
]
],
"normalized": []
},
{
"id": "1598907_T10",
"type": "Gene",
"text": [
"LPL"
],
"offsets": [
[
733,
736
]
],
"normalized": []
},
{
"id": "1598907_T11",
"type": "SNP",
"text": [
"Trp86----Arg"
],
"offsets": [
[
838,
850
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1598907_R1",
"type": "AssociatedTo",
"arg1_id": "1598907_T2",
"arg2_id": "1598907_T1",
"normalized": []
},
{
"id": "1598907_R2",
"type": "Equals",
"arg1_id": "1598907_T3",
"arg2_id": "1598907_T4",
"normalized": []
},
{
"id": "1598907_R3",
"type": "AssociatedTo",
"arg1_id": "1598907_T7",
"arg2_id": "1598907_T5",
"normalized": []
},
{
"id": "1598907_R4",
"type": "AssociatedTo",
"arg1_id": "1598907_T6",
"arg2_id": "1598907_T5",
"normalized": []
},
{
"id": "1598907_R5",
"type": "AssociatedTo",
"arg1_id": "1598907_T8",
"arg2_id": "1598907_T5",
"normalized": []
},
{
"id": "1598907_R6",
"type": "AssociatedTo",
"arg1_id": "1598907_T9",
"arg2_id": "1598907_T5",
"normalized": []
}
] |
117 | 1642234 | [
{
"id": "1642234__text",
"type": "abstract",
"text": [
"Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Nonsyndromic cleft lip with or without cleft palate (CL +/- P) is traditionally recognized as a multifactorial threshold trait (MFT). Recently, however, evidence for the involvement of a major gene in the etiology of CL +/- P has been reported. To assess the potential for major-gene involvement in the etiology of this trait, familial recurrence patterns from several family studies of CL +/- P were reanalyzed. The recurrence patterns in first-degree relatives of CL +/- P probands were found to be compatible with the expectations for either an MFT or a generalized single-major-locus (gSML) trait. The use of multiple thresholds based on proband sex, defect bilaterality, or palatal involvement did not help to discriminate between these models. However, the pattern of recurrence among MZ twins and more remote relatives of CL +/- P probands is not consistent with gSML inheritance but is compatible with either an MFT model or a model specifying multiple interacting loci. For such a model, no single locus can account for more than a sixfold increase in risk to first-degree relatives. These findings have important implications with regard to the feasibility of detecting linkage to loci conferring susceptibility to CL +/- P.\n"
],
"offsets": [
[
0,
1325
]
]
}
] | [] | [] | [] | [] |
118 | 1415228 | [
{
"id": "1415228__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
847
]
]
}
] | [] | [] | [] | [] |
119 | 1550114 | [
{
"id": "1550114__text",
"type": "abstract",
"text": [
"Early British discoveries in human genetics: contributions of R.A. Fisher and J.B.S. Haldane to the development of blood groups.\n"
],
"offsets": [
[
0,
129
]
]
}
] | [] | [] | [] | [] |
120 | 17999359 | [
{
"id": "17999359__text",
"type": "abstract",
"text": [
"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 mutation carriers.\n"
],
"offsets": [
[
0,
1422
]
]
}
] | [
{
"id": "17999359_T1",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
0,
5
]
],
"normalized": []
},
{
"id": "17999359_T2",
"type": "SNP",
"text": [
"135G-->C"
],
"offsets": [
[
6,
14
]
],
"normalized": []
},
{
"id": "17999359_T3",
"type": "Gene",
"text": [
"BRCA2"
],
"offsets": [
[
49,
54
]
],
"normalized": []
},
{
"id": "17999359_T4",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
122,
127
]
],
"normalized": []
},
{
"id": "17999359_T5",
"type": "Gene",
"text": [
"BRCA1"
],
"offsets": [
[
220,
225
]
],
"normalized": []
},
{
"id": "17999359_T6",
"type": "Gene",
"text": [
"BRCA2"
],
"offsets": [
[
230,
235
]
],
"normalized": []
},
{
"id": "17999359_T7",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
315,
320
]
],
"normalized": []
},
{
"id": "17999359_T9",
"type": "Gene",
"text": [
"BRCA1"
],
"offsets": [
[
399,
404
]
],
"normalized": []
},
{
"id": "17999359_T10",
"type": "Gene",
"text": [
"BRCA2"
],
"offsets": [
[
409,
414
]
],
"normalized": []
},
{
"id": "17999359_T11",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
517,
522
]
],
"normalized": []
},
{
"id": "17999359_T12",
"type": "SNP",
"text": [
"135G-->C"
],
"offsets": [
[
523,
531
]
],
"normalized": []
},
{
"id": "17999359_T13",
"type": "Gene",
"text": [
"BRCA1"
],
"offsets": [
[
795,
800
]
],
"normalized": []
},
{
"id": "17999359_T14",
"type": "Gene",
"text": [
"BRCA2"
],
"offsets": [
[
805,
810
]
],
"normalized": []
},
{
"id": "17999359_T15",
"type": "Gene",
"text": [
"BRCA2"
],
"offsets": [
[
915,
920
]
],
"normalized": []
},
{
"id": "17999359_T16",
"type": "SNP",
"text": [
"135G-->C"
],
"offsets": [
[
1142,
1150
]
],
"normalized": []
},
{
"id": "17999359_T17",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
1167,
1172
]
],
"normalized": []
},
{
"id": "17999359_T18",
"type": "SNP",
"text": [
"135G-->C"
],
"offsets": [
[
1207,
1215
]
],
"normalized": []
},
{
"id": "17999359_T19",
"type": "Gene",
"text": [
"BRCA2"
],
"offsets": [
[
1256,
1261
]
],
"normalized": []
},
{
"id": "17999359_T20",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
1310,
1315
]
],
"normalized": []
},
{
"id": "17999359_T21",
"type": "Gene",
"text": [
"BRCA1/2"
],
"offsets": [
[
1395,
1402
]
],
"normalized": []
},
{
"id": "17999359_T22",
"type": "Gene",
"text": [
"RAD51"
],
"offsets": [
[
1317,
1322
]
],
"normalized": []
},
{
"id": "17999359_T8",
"type": "SNP",
"text": [
"135G-->C"
],
"offsets": [
[
322,
330
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17999359_R1",
"type": "AssociatedTo",
"arg1_id": "17999359_T2",
"arg2_id": "17999359_T1",
"normalized": []
},
{
"id": "17999359_R3",
"type": "AssociatedTo",
"arg1_id": "17999359_T12",
"arg2_id": "17999359_T11",
"normalized": []
},
{
"id": "17999359_R2",
"type": "AssociatedTo",
"arg1_id": "17999359_T8",
"arg2_id": "17999359_T7",
"normalized": []
}
] |
121 | 17847000 | [
{
"id": "17847000__text",
"type": "abstract",
"text": [
"Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation. Germline mutations of PTEN (phosphatase and tensin homolog deleted on chromosome 10) are associated with the multihamartomatous disorder Cowden syndrome (CS). Moreover, patients with CS with germline PTEN promoter mutations have aberrant PTEN protein expression and an increased frequency of breast cancer. Here, we examined the downstream effect of five PTEN promoter variants (-861G/T, -853C/G, -834C/T, -798G/C, and -764G/A) that are not within any known cis-acting regulatory elements. Clinically, all five of these patients have been given diagnoses of breast, thyroid, and/or endometrial cancer. We demonstrated that protein binding to the PTEN promoter (-893 to -755) was not altered in the five variants when compared with the wild-type (WT) promoter. However, reporter assays indicated that three of the variants (-861G/T, -853C/G, and -764G/A) demonstrated an ~50% decrease in luciferase activity compared with the WT construct. PTEN messenger RNA (mRNA) levels were not altered in these variants, whereas secondary structure predictions indicated that different PTEN 5' untranslated region transcript-folding patterns exist in three variants, suggesting an inhibition of protein translation. This was confirmed by PTEN protein analysis. These data indicate that variants causing large mRNA secondary structure alterations result in an inhibition of protein translation and a decrease in PTEN protein expression. These data emphasize the importance of PTEN promoter nucleotide variations and their ability to lead to CS progression by a novel regulatory mechanism. Importantly, these patients have a high prevalence of breast, thyroid, and endometrial malignancies; thus, understanding of the mechanism of PTEN dysfunction in these patients will lead to more-sensitive molecular diagnostic and predictive testing and, ultimately, to rational targeted therapies to treat or prevent malignancy.\n"
],
"offsets": [
[
0,
2008
]
]
}
] | [
{
"id": "17847000_T1",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
39,
43
]
],
"normalized": []
},
{
"id": "17847000_T2",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
127,
131
]
],
"normalized": []
},
{
"id": "17847000_T3",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
305,
309
]
],
"normalized": []
},
{
"id": "17847000_T4",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
343,
347
]
],
"normalized": []
},
{
"id": "17847000_T5",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
460,
464
]
],
"normalized": []
},
{
"id": "17847000_T6",
"type": "SNP",
"text": [
"-861G/T"
],
"offsets": [
[
484,
491
]
],
"normalized": []
},
{
"id": "17847000_T7",
"type": "SNP",
"text": [
"-853C/G"
],
"offsets": [
[
493,
500
]
],
"normalized": []
},
{
"id": "17847000_T8",
"type": "SNP",
"text": [
"-834C/T"
],
"offsets": [
[
502,
509
]
],
"normalized": []
},
{
"id": "17847000_T9",
"type": "SNP",
"text": [
"-798G/C"
],
"offsets": [
[
511,
518
]
],
"normalized": []
},
{
"id": "17847000_T10",
"type": "SNP",
"text": [
"-764G/A"
],
"offsets": [
[
524,
531
]
],
"normalized": []
},
{
"id": "17847000_T11",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
751,
755
]
],
"normalized": []
},
{
"id": "17847000_T12",
"type": "SNP",
"text": [
"-861G/T"
],
"offsets": [
[
928,
935
]
],
"normalized": []
},
{
"id": "17847000_T13",
"type": "SNP",
"text": [
"-853C/G"
],
"offsets": [
[
937,
944
]
],
"normalized": []
},
{
"id": "17847000_T14",
"type": "SNP",
"text": [
"-764G/A"
],
"offsets": [
[
950,
957
]
],
"normalized": []
},
{
"id": "17847000_T15",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
1044,
1048
]
],
"normalized": []
},
{
"id": "17847000_T16",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
1178,
1182
]
],
"normalized": []
},
{
"id": "17847000_T17",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
1330,
1334
]
],
"normalized": []
},
{
"id": "17847000_T18",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
1503,
1507
]
],
"normalized": []
},
{
"id": "17847000_T19",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
1567,
1571
]
],
"normalized": []
},
{
"id": "17847000_T20",
"type": "Gene",
"text": [
"PTEN"
],
"offsets": [
[
1821,
1825
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17847000_R1",
"type": "AssociatedTo",
"arg1_id": "17847000_T6",
"arg2_id": "17847000_T5",
"normalized": []
},
{
"id": "17847000_R2",
"type": "AssociatedTo",
"arg1_id": "17847000_T7",
"arg2_id": "17847000_T5",
"normalized": []
},
{
"id": "17847000_R3",
"type": "AssociatedTo",
"arg1_id": "17847000_T8",
"arg2_id": "17847000_T5",
"normalized": []
},
{
"id": "17847000_R4",
"type": "AssociatedTo",
"arg1_id": "17847000_T9",
"arg2_id": "17847000_T5",
"normalized": []
},
{
"id": "17847000_R5",
"type": "AssociatedTo",
"arg1_id": "17847000_T10",
"arg2_id": "17847000_T5",
"normalized": []
}
] |
122 | 17503325 | [
{
"id": "17503325__text",
"type": "abstract",
"text": [
"Red-green color vision impairment in Duchenne muscular dystrophy. The present study evaluated the color vision of 44 patients with Duchenne muscular dystrophy (DMD) (mean age 14.8 years; SD 4.9) who were submitted to a battery of four different color tests: Cambridge Colour Test (CCT), Neitz Anomaloscope, Ishihara, and American Optical Hardy-Rand-Rittler (AO H-R-R). Patients were divided into two groups according to the region of deletion in the dystrophin gene: upstream of exon 30 (n=12) and downstream of exon 30 (n=32). The control group was composed of 70 age-matched healthy male subjects with no ophthalmological complaints. Of the patients with DMD, 47% (21/44) had a red-green color vision defect in the CCT, confirmed by the Neitz Anomaloscope with statistical agreement (P<.001). The Ishihara and the AO H-R-R had a lower capacity to detect color defects--5% and 7%, respectively, with no statistical similarity between the results of these two tests nor between CCT and Anomaloscope results (P>.05). Of the patients with deletion downstream of exon 30, 66% had a red-green color defect. No color defect was found in the patients with deletion upstream of exon 30. A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. The percentage (66%) of patients with a red-green defect was significantly higher than the expected <10% for the normal male population (P<.001). In contrast, patients with DMD with deletion upstream of exon 30 had normal color vision. This color defect might be partially explained by a retina impairment related to dystrophin isoform Dp260.\n"
],
"offsets": [
[
0,
1675
]
]
}
] | [
{
"id": "17503325_T1",
"type": "Gene",
"text": [
"dystrophin"
],
"offsets": [
[
450,
460
]
],
"normalized": []
},
{
"id": "17503325_T2",
"type": "Gene",
"text": [
"dystrophin"
],
"offsets": [
[
1649,
1659
]
],
"normalized": []
}
] | [] | [] | [] |
123 | 17436244 | [
{
"id": "17436244__text",
"type": "abstract",
"text": [
"Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a key role in DNA double-strand-type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with FA from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3%-6% of FA-affected patients registered in various data sets. Malformations are frequent in FA-D2 patients, and hematological manifestations appear earlier and progress more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. FANCD2 is flanked by two pseudogenes. Mutation analysis revealed the expected total of 66 mutated alleles, 34 of which result in aberrant splicing patterns. Many mutations are recurrent and have ethnic associations and shared allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggest that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA.\n"
],
"offsets": [
[
0,
1465
]
]
}
] | [
{
"id": "17436244_T1",
"type": "Gene",
"text": [
"Fanconi anemia protein"
],
"offsets": [
[
49,
71
]
],
"normalized": []
},
{
"id": "17436244_T2",
"type": "Gene",
"text": [
"FANCD2"
],
"offsets": [
[
73,
79
]
],
"normalized": []
},
{
"id": "17436244_T3",
"type": "Gene",
"text": [
"FANCD2"
],
"offsets": [
[
150,
156
]
],
"normalized": []
},
{
"id": "17436244_T4",
"type": "Gene",
"text": [
"FANCD2"
],
"offsets": [
[
791,
797
]
],
"normalized": []
},
{
"id": "17436244_T5",
"type": "Gene",
"text": [
"FANCD2"
],
"offsets": [
[
1086,
1092
]
],
"normalized": []
},
{
"id": "17436244_T6",
"type": "Gene",
"text": [
"FANCD2"
],
"offsets": [
[
1247,
1253
]
],
"normalized": []
},
{
"id": "17436244_T7",
"type": "Gene",
"text": [
"FANCD2"
],
"offsets": [
[
1337,
1343
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17436244_R1",
"type": "Equals",
"arg1_id": "17436244_T1",
"arg2_id": "17436244_T2",
"normalized": []
}
] |
124 | 17503322 | [
{
"id": "17503322__text",
"type": "abstract",
"text": [
"A genomewide admixture map for Latino populations. Admixture mapping is an economical and powerful approach for localizing disease genes in populations of recently mixed ancestry and has proven successful in African Americans. The method holds equal promise for Latinos, who typically inherit a mix of European, Native American, and African ancestry. However, admixture mapping in Latinos has not been practical because of the lack of a map of ancestry-informative markers validated in Native American and other populations. To address this, we screened multiple databases, containing millions of markers, to identify 4,186 markers that were putatively informative for determining the ancestry of chromosomal segments in Latino populations. We experimentally validated each of these markers in at least 232 new Latino, European, Native American, and African samples, and we selected a subset of 1,649 markers to form an admixture map. An advantage of our strategy is that we focused our map on markers distinguishing Native American from other ancestries and restricted it to markers with very similar frequencies in Europeans and Africans, which decreased the number of markers needed and minimized the possibility of false disease associations. We evaluated the effectiveness of our map for localizing disease genes in four Latino populations from both North and South America.\n"
],
"offsets": [
[
0,
1380
]
]
}
] | [] | [] | [] | [] |
125 | 17847001 | [
{
"id": "17847001__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1345
]
]
}
] | [
{
"id": "17847001_T1",
"type": "Gene",
"text": [
"MBD5"
],
"offsets": [
[
1082,
1086
]
],
"normalized": []
},
{
"id": "17847001_T2",
"type": "Gene",
"text": [
"methyl-CpG-binding domain protein 5"
],
"offsets": [
[
1108,
1143
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17847001_R1",
"type": "Equals",
"arg1_id": "17847001_T2",
"arg2_id": "17847001_T1",
"normalized": []
}
] |
126 | 17436254 | [
{
"id": "17436254__text",
"type": "abstract",
"text": [
"Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Pitt-Hopkins syndrome (PHS) is a rare syndromic encephalopathy characterized by daily bouts of hyperventilation and a facial gestalt. We report a 1.8-Mb de novo microdeletion on chromosome 18q21.1, identified by array-comparative genomic hybridization in one patient with PHS. We subsequently identified two de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene in three additional subjects with PHS. These findings demonstrate that TCF4 anomalies are responsible for PHS and provide the first evidence of a human disorder related to class I basic helix-loop-helix transcription-factor defects (also known as \"E proteins\"). Moreover, our data may shed new light on the normal processes underlying autonomic nervous system development and maintenance of an appropriate ventilatory neuronal circuitry.\n"
],
"offsets": [
[
0,
1048
]
]
}
] | [
{
"id": "17436254_T1",
"type": "Gene",
"text": [
"TCF4"
],
"offsets": [
[
13,
17
]
],
"normalized": []
},
{
"id": "17436254_T2",
"type": "Gene",
"text": [
"TCF4"
],
"offsets": [
[
600,
604
]
],
"normalized": []
},
{
"id": "17436254_T3",
"type": "Gene",
"text": [
"TCF4"
],
"offsets": [
[
681,
685
]
],
"normalized": []
}
] | [] | [] | [] |
127 | 17999356 | [
{
"id": "17999356__text",
"type": "abstract",
"text": [
"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 deficiency and exemplifies the integration of molecular information in a therapeutic strategy.\n"
],
"offsets": [
[
0,
2240
]
]
}
] | [
{
"id": "17999356_T1",
"type": "Gene",
"text": [
"Very-long-chain acyl-coenzyme A dehydrogenase"
],
"offsets": [
[
161,
206
]
],
"normalized": []
},
{
"id": "17999356_T2",
"type": "Gene",
"text": [
"VLCAD"
],
"offsets": [
[
208,
213
]
],
"normalized": []
},
{
"id": "17999356_T3",
"type": "Gene",
"text": [
"VLCAD"
],
"offsets": [
[
1476,
1481
]
],
"normalized": []
},
{
"id": "17999356_T4",
"type": "Gene",
"text": [
"VLCAD"
],
"offsets": [
[
2139,
2144
]
],
"normalized": []
},
{
"id": "17999356_T5",
"type": "Gene",
"text": [
"VLCAD"
],
"offsets": [
[
1348,
1353
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17999356_R1",
"type": "Equals",
"arg1_id": "17999356_T1",
"arg2_id": "17999356_T2",
"normalized": []
}
] |
128 | 17503333 | [
{
"id": "17503333__text",
"type": "abstract",
"text": [
"RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Carpenter syndrome is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling. In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicates HH signaling in cranial-suture biogenesis--an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components--and provides a new molecular target for studies of obesity.\n"
],
"offsets": [
[
0,
1385
]
]
}
] | [
{
"id": "17503333_T1",
"type": "Gene",
"text": [
"RAB23"
],
"offsets": [
[
0,
5
]
],
"normalized": []
},
{
"id": "17503333_T2",
"type": "Gene",
"text": [
"RAB23"
],
"offsets": [
[
492,
497
]
],
"normalized": []
},
{
"id": "17503333_T3",
"type": "SNP",
"text": [
"L145X"
],
"offsets": [
[
752,
757
]
],
"normalized": []
},
{
"id": "17503333_T4",
"type": "Gene",
"text": [
"Rab23"
],
"offsets": [
[
904,
909
]
],
"normalized": []
},
{
"id": "17503333_T5",
"type": "Gene",
"text": [
"RAB23"
],
"offsets": [
[
1046,
1051
]
],
"normalized": []
},
{
"id": "17503333_T6",
"type": "Gene",
"text": [
"RAB23"
],
"offsets": [
[
1095,
1100
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17503333_R1",
"type": "AssociatedTo",
"arg1_id": "17503333_T3",
"arg2_id": "17503333_T4",
"normalized": []
}
] |
129 | 17503332 | [
{
"id": "17503332__text",
"type": "abstract",
"text": [
"Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.\n"
],
"offsets": [
[
0,
2010
]
]
}
] | [
{
"id": "17503332_T1",
"type": "Gene",
"text": [
"TCF7L2"
],
"offsets": [
[
16,
22
]
],
"normalized": []
},
{
"id": "17503332_T2",
"type": "Gene",
"text": [
"TCF7L2"
],
"offsets": [
[
502,
508
]
],
"normalized": []
},
{
"id": "17503332_T3",
"type": "SNP",
"text": [
"-30G-->A"
],
"offsets": [
[
1502,
1510
]
],
"normalized": []
}
] | [] | [] | [] |
130 | 17273962 | [
{
"id": "17273962__text",
"type": "abstract",
"text": [
"Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Because mitochondria play pivotal roles in both insulin secretion from the pancreatic beta cells and insulin resistance of skeletal muscles, we performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type 2 diabetes mellitus (T2DM). The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with T2DM and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with T2DM and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups (i.e., F, B, A, N9a, M7a, M7b, G, D4a, D4b, and D5). Multivariate logistic-regression analysis with adjustment for age and sex revealed that the mitochondrial haplogroup N9a was significantly associated with resistance against T2DM (P=.0002) with an odds ratio of 0.55 (95% confidence interval 0.40-0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplogroup might confer resistance against T2DM.\n"
],
"offsets": [
[
0,
1230
]
]
}
] | [] | [] | [] | [] |
131 | 17160901 | [
{
"id": "17160901__text",
"type": "abstract",
"text": [
"An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA-->ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.\n"
],
"offsets": [
[
0,
1646
]
]
}
] | [
{
"id": "17160901_T1",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
96,
99
]
],
"normalized": []
},
{
"id": "17160901_T2",
"type": "SNP",
"text": [
"c.2970-2972 delAAT"
],
"offsets": [
[
106,
124
]
],
"normalized": []
},
{
"id": "17160901_T3",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
164,
167
]
],
"normalized": []
},
{
"id": "17160901_T4",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
226,
229
]
],
"normalized": []
},
{
"id": "17160901_T5",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
385,
388
]
],
"normalized": []
},
{
"id": "17160901_T6",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
541,
544
]
],
"normalized": []
},
{
"id": "17160901_T7",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
639,
642
]
],
"normalized": []
},
{
"id": "17160901_T8",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
685,
688
]
],
"normalized": []
},
{
"id": "17160901_T9",
"type": "SNP",
"text": [
"c.2970-2972 delAAT"
],
"offsets": [
[
760,
778
]
],
"normalized": []
},
{
"id": "17160901_T10",
"type": "SNP",
"text": [
"p.990delM"
],
"offsets": [
[
780,
789
]
],
"normalized": []
},
{
"id": "17160901_T11",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
978,
981
]
],
"normalized": []
},
{
"id": "17160901_T13",
"type": "SNP",
"text": [
"ACA-->ACG change of codon 990"
],
"offsets": [
[
1169,
1198
]
],
"normalized": []
},
{
"id": "17160901_T14",
"type": "Gene",
"text": [
"NF1"
],
"offsets": [
[
1453,
1456
]
],
"normalized": []
},
{
"id": "17160901_T12",
"type": "SNP",
"text": [
"c.2970-2972 delAAT"
],
"offsets": [
[
940,
958
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17160901_R1",
"type": "AssociatedTo",
"arg1_id": "17160901_T2",
"arg2_id": "17160901_T1",
"normalized": []
},
{
"id": "17160901_R2",
"type": "AssociatedTo",
"arg1_id": "17160901_T9",
"arg2_id": "17160901_T8",
"normalized": []
},
{
"id": "17160901_R3",
"type": "AssociatedTo",
"arg1_id": "17160901_T10",
"arg2_id": "17160901_T8",
"normalized": []
},
{
"id": "17160901_R4",
"type": "AssociatedTo",
"arg1_id": "17160901_T12",
"arg2_id": "17160901_T11",
"normalized": []
}
] |
132 | 17436249 | [
{
"id": "17436249__text",
"type": "abstract",
"text": [
"Measuring European population stratification with microarray genotype data. A proper understanding of population genetic stratification--differences in individual ancestry within a population--is crucial in attempts to find genes for complex traits through association mapping. We report on genomewide typing of approximately 10,000 single-nucleotide polymorphisms in 297 individuals, to explore population structure in Europeans of known and unknown ancestry. The results reveal the presence of several significant axes of stratification, most prominently in a northern-southeastern trend, but also along an east-west axis. We also demonstrate the selection and application of EuroAIMs (European ancestry informative markers) for ancestry estimation and correction. The Coriell Caucasian and CEPH (Centre d'Etude du Polymorphisme Humain) Utah sample panels, often used as proxies for European populations, are found to reflect different subsets of the continent's ancestry.\n"
],
"offsets": [
[
0,
975
]
]
}
] | [] | [] | [] | [] |
133 | 17160889 | [
{
"id": "17160889__text",
"type": "abstract",
"text": [
"Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.\n"
],
"offsets": [
[
0,
1809
]
]
}
] | [
{
"id": "17160889_T1",
"type": "Gene",
"text": [
"BBS12"
],
"offsets": [
[
36,
41
]
],
"normalized": []
},
{
"id": "17160889_T2",
"type": "Gene",
"text": [
"BBS12"
],
"offsets": [
[
603,
608
]
],
"normalized": []
},
{
"id": "17160889_T3",
"type": "Gene",
"text": [
"FLJ35630"
],
"offsets": [
[
715,
723
]
],
"normalized": []
},
{
"id": "17160889_T4",
"type": "Gene",
"text": [
"BBS6"
],
"offsets": [
[
884,
888
]
],
"normalized": []
},
{
"id": "17160889_T5",
"type": "Gene",
"text": [
"BBS10"
],
"offsets": [
[
893,
898
]
],
"normalized": []
},
{
"id": "17160889_T6",
"type": "Gene",
"text": [
"BBS12"
],
"offsets": [
[
1033,
1038
]
],
"normalized": []
},
{
"id": "17160889_T7",
"type": "Gene",
"text": [
"BBS12"
],
"offsets": [
[
1087,
1092
]
],
"normalized": []
},
{
"id": "17160889_T8",
"type": "Gene",
"text": [
"BBS6"
],
"offsets": [
[
1135,
1139
]
],
"normalized": []
},
{
"id": "17160889_T9",
"type": "Gene",
"text": [
"BBS10"
],
"offsets": [
[
1144,
1149
]
],
"normalized": []
}
] | [] | [] | [] |
134 | 17571465 | [
{
"id": "17571465__text",
"type": "abstract",
"text": [
"Arthur G. Steinberg, 1912-2006.\n"
],
"offsets": [
[
0,
32
]
]
}
] | [] | [] | [] | [] |
135 | 17701907 | [
{
"id": "17701907__text",
"type": "abstract",
"text": [
"Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans. A single-nucleotide variant, C/T(-13910), located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T(-13910) variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8-H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T(-13910) H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T(-13910) H98 allele (approximately 5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (approximately 1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T(-13910) allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans.\n"
],
"offsets": [
[
0,
1422
]
]
}
] | [
{
"id": "17701907_T1",
"type": "SNP",
"text": [
"C/T(-13910)"
],
"offsets": [
[
131,
142
]
],
"normalized": []
},
{
"id": "17701907_T2",
"type": "Gene",
"text": [
"lactase"
],
"offsets": [
[
174,
181
]
],
"normalized": []
},
{
"id": "17701907_T3",
"type": "Gene",
"text": [
"LCT"
],
"offsets": [
[
188,
191
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17701907_R1",
"type": "Equals",
"arg1_id": "17701907_T2",
"arg2_id": "17701907_T3",
"normalized": []
}
] |
136 | 17668385 | [
{
"id": "17668385__text",
"type": "abstract",
"text": [
"Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain-containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.\n"
],
"offsets": [
[
0,
837
]
]
}
] | [
{
"id": "17668385_T1",
"type": "Gene",
"text": [
"BRWD3"
],
"offsets": [
[
17,
22
]
],
"normalized": []
},
{
"id": "17668385_T2",
"type": "Gene",
"text": [
"BRWD3,"
],
"offsets": [
[
295,
301
]
],
"normalized": []
},
{
"id": "17668385_T3",
"type": "Gene",
"text": [
"BRWD3"
],
"offsets": [
[
642,
647
]
],
"normalized": []
}
] | [] | [] | [] |
137 | 17924341 | [
{
"id": "17924341__text",
"type": "abstract",
"text": [
"Fine mapping versus replication in whole-genome association studies. Association replication studies have a poor track record and, even when successful, often claim association with different markers, alleles, and phenotypes than those reported in the primary study. It is unknown whether these outcomes reflect genuine associations or false-positive results. A greater understanding of these observations is essential for genomewide association (GWA) studies, since they have the potential to identify multiple new associations that that will require external validation. Theoretically, a repeat association with precisely the same variant in an independent sample is the gold standard for replication, but testing additional variants is commonplace in replication studies. Finding different associated SNPs within the same gene or region as that originally identified is often reported as confirmatory evidence. Here, we compare the probability of replicating a gene or region under two commonly used marker-selection strategies: an \"exact\" approach that involves only the originally significant markers and a \"local\" approach that involves both the originally significant markers and others in the same region. When a region of high intermarker linkage disequilibrium is tested to replicate an initial finding that is only weak association with disease, the local approach is a good strategy. Otherwise, the most powerful and efficient strategy for replication involves testing only the initially identified variants. Association with a marker other than that originally identified can occur frequently, even in the presence of real effects in a low-powered replication study, and instances of such association increase as the number of included variants increases. Our results provide a basis for the design and interpretation of GWA replication studies and point to the importance of a clear distinction between fine mapping and replication after GWA.\n"
],
"offsets": [
[
0,
1957
]
]
}
] | [] | [] | [] | [] |
138 | 17236129 | [
{
"id": "17236129__text",
"type": "abstract",
"text": [
"Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).\n"
],
"offsets": [
[
0,
1377
]
]
}
] | [] | [] | [] | [] |
139 | 17357082 | [
{
"id": "17357082__text",
"type": "abstract",
"text": [
"Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms. To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease.\n"
],
"offsets": [
[
0,
1175
]
]
}
] | [
{
"id": "17357082_T1",
"type": "Gene",
"text": [
"MAPT"
],
"offsets": [
[
165,
169
]
],
"normalized": []
},
{
"id": "17357082_T2",
"type": "Gene",
"text": [
"MAPT"
],
"offsets": [
[
640,
644
]
],
"normalized": []
},
{
"id": "17357082_T3",
"type": "Gene",
"text": [
"DNA damage-binding protein 2"
],
"offsets": [
[
921,
949
]
],
"normalized": []
},
{
"id": "17357082_T4",
"type": "Gene",
"text": [
"DDB2"
],
"offsets": [
[
951,
955
]
],
"normalized": []
},
{
"id": "17357082_T5",
"type": "Gene",
"text": [
"lysosomal acid phosphatase 2"
],
"offsets": [
[
961,
989
]
],
"normalized": []
},
{
"id": "17357082_T6",
"type": "Gene",
"text": [
"ACP2"
],
"offsets": [
[
991,
995
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17357082_R1",
"type": "Equals",
"arg1_id": "17357082_T3",
"arg2_id": "17357082_T4",
"normalized": []
},
{
"id": "17357082_R2",
"type": "Equals",
"arg1_id": "17357082_T5",
"arg2_id": "17357082_T6",
"normalized": []
}
] |
140 | 12717633 | [
{
"id": "12717633__text",
"type": "abstract",
"text": [
"A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.\n"
],
"offsets": [
[
0,
1257
]
]
}
] | [] | [] | [] | [] |
141 | 12618959 | [
{
"id": "12618959__text",
"type": "abstract",
"text": [
"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 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.\n"
],
"offsets": [
[
0,
1474
]
]
}
] | [
{
"id": "12618959_T1",
"type": "Gene",
"text": [
"lamin B receptor"
],
"offsets": [
[
141,
157
]
],
"normalized": []
},
{
"id": "12618959_T2",
"type": "Gene",
"text": [
"3beta-hydroxysterol delta(14)-reductase"
],
"offsets": [
[
584,
623
]
],
"normalized": []
},
{
"id": "12618959_T3",
"type": "SNP",
"text": [
"1599-1605TCTTCTA-->CTAGAAG"
],
"offsets": [
[
759,
785
]
],
"normalized": []
},
{
"id": "12618959_T4",
"type": "Gene",
"text": [
"LBR"
],
"offsets": [
[
817,
820
]
],
"normalized": []
},
{
"id": "12618959_T5",
"type": "Gene",
"text": [
"human sterol delta(14)-reductases"
],
"offsets": [
[
684,
717
]
],
"normalized": []
},
{
"id": "12618959_T6",
"type": "Gene",
"text": [
"TM7SF2"
],
"offsets": [
[
719,
725
]
],
"normalized": []
},
{
"id": "12618959_T7",
"type": "Gene",
"text": [
"LBR"
],
"offsets": [
[
730,
733
]
],
"normalized": []
},
{
"id": "12618959_T8",
"type": "Gene",
"text": [
"LBR"
],
"offsets": [
[
992,
995
]
],
"normalized": []
},
{
"id": "12618959_T9",
"type": "Gene",
"text": [
"LBR"
],
"offsets": [
[
1059,
1062
]
],
"normalized": []
},
{
"id": "12618959_T10",
"type": "Gene",
"text": [
"3beta-hydroxysterol delta(14)-reductase"
],
"offsets": [
[
1422,
1461
]
],
"normalized": []
}
] | [] | [] | [] |
142 | 12900794 | [
{
"id": "12900794__text",
"type": "abstract",
"text": [
"A full-likelihood method for the evaluation of causality of sequence variants from family data. In many disease genes, a substantial fraction of all rare variants detected cannot yet be used for genetic counselling because of uncertainty about their association with disease. One approach to the characterization of these unclassified variants is the analysis of patterns of cosegregation with disease in affected carrier families. Petersen et al. previously provided a simplistic Bayesian method for evaluation of causality of such sequence variants. In the present report, we propose a more general method based on the full pedigree likelihood, and we show that the use of this method can provide more accurate and informative assessment of causality than could the previous method. We further show that it is important that the pedigree information be as complete as possible and that the distinction be made between unaffected individuals and those of unknown phenotype.\n"
],
"offsets": [
[
0,
975
]
]
}
] | [] | [] | [] | [] |
143 | 12687497 | [
{
"id": "12687497__text",
"type": "abstract",
"text": [
"A family-based test for correlation between gene expression and trait values. Advances in microarray technology have made it attractive to combine information on clinical traits, marker genotypes, and comprehensive gene expression from family studies to dissect complex disease genetics. Without accounting for family structure, methods that test for association between a trait and gene-expression levels can be misleading. We demonstrate that the standard unstratified test based on Pearson's correlation coefficient can produce spurious results when applied to family data, and we present a stratified family expression association test (FEXAT). We illustrate the utility of the FEXAT via simulation and an application to gene-expression data from lymphoblastoid cell lines from four CEPH families. The FEXAT has a smaller estimated false-discovery rate than the standard test when within-family correlations are of interest, and it detects biologically plausible correlations between beta catenin and genes in the WNT-activation pathway in humans that the standard test does not.\n"
],
"offsets": [
[
0,
1084
]
]
}
] | [] | [] | [] | [] |
144 | 12474146 | [
{
"id": "12474146__text",
"type": "abstract",
"text": [
"A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. Several genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.\n"
],
"offsets": [
[
0,
1415
]
]
}
] | [] | [] | [] | [] |
145 | 13680528 | [
{
"id": "13680528__text",
"type": "abstract",
"text": [
"A genomewide screen of 345 families for autism-susceptibility loci. We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20). In this follow-up analysis we have increased the sample size threefold, while holding the study design constant, so that we now report 345 multiplex families, each with at least two siblings affected with autism or ASD phenotype. Along with 235 new multiplex families, 73 new microsatellite markers were also added in 10 regions, thereby increasing the marker density at these strategic locations from 10 cM to approximately 2 cM and bringing the total number of markers to 408 over the entire genome. Multipoint maximum LOD scores (MLS) obtained from affected-sib-pair analysis of all 345 families yielded suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order by MLS) (P <.01). The most significant findings were an MLS of 2.83 (P =.00029) on chromosome 17q, near the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), and an MLS of 2.54 (P =.00059) on 5p. The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions.\n"
],
"offsets": [
[
0,
1647
]
]
}
] | [] | [] | [] | [] |
146 | 12506336 | [
{
"id": "12506336__text",
"type": "abstract",
"text": [
"CD36 polymorphism is associated with protection from cerebral malaria. The human protein CD36 is a major receptor for Plasmodium falciparum-infected erythrocytes and contributes to the pathology of P. falciparum malaria. We performed variation screening of the CD36 gene and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with P. falciparum malaria. Accordingly, we identified nine CD36 polymorphisms with a high-frequency (>15%) minor allele. Of these, the frequencies of the -14T-->C allele in the upstream promoter region and the -53G-->T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared to those with mild malaria (P=.016 for -14T-->C and P=.050 for -53G-->T). The analysis of linkage disequilibrium (LD) between the nine common polymorphisms revealed that there are two blocks with strong LD in the CD36 gene and that the -14T-->C and -53G-->T polymorphisms are within the upstream block of 35 kb from the upstream promoter to exon 8. Further association testing after the second variation screening in the upstream block indicated that the in3(TG)(12) (i.e., 12 TG repeats in intron 3) allele is most strongly associated with the reduction in the risk of cerebral malaria (odds ratio 0.59; 95% confidence interval 0.40-0.87; P=.0069). We found, by reverse-transcriptase PCR amplification, that in3(TG)(12) is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Since exon 5 of the gene is known to encode the ligand-binding domain for P. falciparum-infected erythrocytes, in3(TG)(12) itself or a primary variant on the haplotype with in3(TG)(12) may be responsible for protection from cerebral malaria in Thailand. Results of the present study suggest that LD mapping has potential for detecting a disease-associated variant on the basis of haplotype blocks.\n"
],
"offsets": [
[
0,
1933
]
]
}
] | [
{
"id": "12506336_T1",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
0,
4
]
],
"normalized": []
},
{
"id": "12506336_T2",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
89,
93
]
],
"normalized": []
},
{
"id": "12506336_T3",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
261,
265
]
],
"normalized": []
},
{
"id": "12506336_T4",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
317,
321
]
],
"normalized": []
},
{
"id": "12506336_T5",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
451,
455
]
],
"normalized": []
},
{
"id": "12506336_T8",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
937,
941
]
],
"normalized": []
},
{
"id": "12506336_T9",
"type": "Gene",
"text": [
"CD36"
],
"offsets": [
[
1493,
1497
]
],
"normalized": []
},
{
"id": "12506336_T10",
"type": "SNP",
"text": [
"-14T-->C"
],
"offsets": [
[
960,
968
]
],
"normalized": []
},
{
"id": "12506336_T11",
"type": "SNP",
"text": [
"-53G-->T"
],
"offsets": [
[
973,
981
]
],
"normalized": []
},
{
"id": "12506336_T12",
"type": "SNP",
"text": [
"-14T-->C"
],
"offsets": [
[
763,
771
]
],
"normalized": []
},
{
"id": "12506336_T13",
"type": "SNP",
"text": [
"-53G-->T"
],
"offsets": [
[
787,
795
]
],
"normalized": []
},
{
"id": "12506336_T6",
"type": "SNP",
"text": [
"-53G-->T"
],
"offsets": [
[
602,
610
]
],
"normalized": []
},
{
"id": "12506336_T7",
"type": "SNP",
"text": [
"-14T-->C"
],
"offsets": [
[
546,
554
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12506336_R1",
"type": "AssociatedTo",
"arg1_id": "12506336_T7",
"arg2_id": "12506336_T5",
"normalized": []
},
{
"id": "12506336_R2",
"type": "AssociatedTo",
"arg1_id": "12506336_T6",
"arg2_id": "12506336_T5",
"normalized": []
}
] |
147 | 12796855 | [
{
"id": "12796855__text",
"type": "abstract",
"text": [
"Selection of genetic markers for association analyses, using linkage disequilibrium and haplotypes. The genotyping of closely spaced single-nucleotide polymorphism (SNP) markers frequently yields highly correlated data, owing to extensive linkage disequilibrium (LD) between markers. The extent of LD varies widely across the genome and drives the number of frequent haplotypes observed in small regions. Several studies have illustrated the possibility that LD or haplotype data could be used to select a subset of SNPs that optimize the information retained in a genomic region while reducing the genotyping effort and simplifying the analysis. We propose a method based on the spectral decomposition of the matrices of pairwise LD between markers, and we select markers on the basis of their contributions to the total genetic variation. We also modify Clayton's \"haplotype tagging SNP\" selection method, which utilizes haplotype information. For both methods, we propose sliding window-based algorithms that allow the methods to be applied to large chromosomal regions. Our procedures require genotype information about a small number of individuals for an initial set of SNPs and selection of an optimum subset of SNPs that could be efficiently genotyped on larger numbers of samples while retaining most of the genetic variation in samples. We identify suitable parameter combinations for the procedures, and we show that a sample size of 50-100 individuals achieves consistent results in studies of simulated data sets in linkage equilibrium and LD. When applied to experimental data sets, both procedures were similarly effective at reducing the genotyping requirement while maintaining the genetic information content throughout the regions. We also show that haplotype-association results that Hosking et al. obtained near CYP2D6 were almost identical before and after marker selection.\n"
],
"offsets": [
[
0,
1897
]
]
}
] | [
{
"id": "12796855_T1",
"type": "Gene",
"text": [
"CYP2D6"
],
"offsets": [
[
1833,
1839
]
],
"normalized": []
}
] | [] | [] | [] |
148 | 12740763 | [
{
"id": "12740763__text",
"type": "abstract",
"text": [
"Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. Uric acid nephrolithiasis (UAN) is a common disease with an established genetic component that presents a complex mode of inheritance. While studying an ancient founder population in Talana, a village in Sardinia, we recently identified a susceptibility locus of approximately 2.5 cM for UAN on 10q21-q22 in a relatively small sample that was carefully selected through genealogical information. To refine the critical region and to identify the susceptibility gene, we extended our analysis to severely affected subjects from the same village. We confirm the involvement of this region in UAN through identical-by-descent sharing and autozygosity mapping, and we refine the critical region to an interval of approximately 67 kb associated with UAN by linkage-disequilibrium mapping. After inspecting the genomic sequences available in public databases, we determined that a novel gene overlaps this interval. This gene is divided into 15 exons, spanning a region of approximately 300 kb and generating at least four different proteins (407, 333, 462, and 216 amino acids). Interestingly, the last isoform was completely included in the 67-kb associated interval. Computer-assisted analysis of this isoform revealed at least one membrane-spanning domain and several N- and O-glycosylation consensus sites at N-termini, suggesting that it could be an integral membrane protein. Mutational analysis shows that a coding nucleotide variant (Ala62Thr), causing a missense in exon 12, is in strong association with UAN (P=.0051). Moreover, Ala62Thr modifies predicted protein secondary structure, suggesting that it may have a role in UAN etiology. The present study underscores the value of our small, genealogically well-characterized, isolated population as a model for the identification of susceptibility genes underlying complex diseases. Indeed, using a relatively small sample of affected and unaffected subjects, we identified a candidate gene for multifactorial UAN.\n"
],
"offsets": [
[
0,
2097
]
]
}
] | [
{
"id": "12740763_T1",
"type": "SNP",
"text": [
"Ala62Thr"
],
"offsets": [
[
1563,
1571
]
],
"normalized": []
},
{
"id": "12740763_T2",
"type": "SNP",
"text": [
"Ala62Thr"
],
"offsets": [
[
1660,
1668
]
],
"normalized": []
}
] | [] | [] | [] |
149 | 12687502 | [
{
"id": "12687502__text",
"type": "abstract",
"text": [
"Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome. Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.\n"
],
"offsets": [
[
0,
1354
]
]
}
] | [
{
"id": "12687502_T1",
"type": "Gene",
"text": [
"NSD1"
],
"offsets": [
[
431,
435
]
],
"normalized": []
},
{
"id": "12687502_T2",
"type": "Gene",
"text": [
"NSD1"
],
"offsets": [
[
527,
531
]
],
"normalized": []
},
{
"id": "12687502_T3",
"type": "Gene",
"text": [
"NSD1"
],
"offsets": [
[
573,
577
]
],
"normalized": []
}
] | [] | [] | [] |
150 | 12587094 | [
{
"id": "12587094__text",
"type": "abstract",
"text": [
"Use of multivariate linkage analysis for dissection of a complex cognitive trait. Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits.\n"
],
"offsets": [
[
0,
1284
]
]
}
] | [] | [] | [] | [] |
151 | 14610717 | [
{
"id": "14610717__text",
"type": "abstract",
"text": [
"Allelic heterogeneity in LINE-1 retrotransposition activity. De novo LINE-1 (long interspersed element-1, or L1) retrotransposition events are responsible for approximately 1/1,000 disease-causing mutations in humans. Previously, L1.2 was identified as the likely progenitor of a mutagenic insertion in the factor VIII gene in a patient with hemophilia A. It subsequently was shown to be one of a small number of active L1s in the human genome. Here, we demonstrate that L1.2 is present at an intermediate insertion allele frequency in worldwide human populations and that common alleles (L1.2A and L1.2B) exhibit an approximately 16-fold difference in their ability to retrotranspose in cultured human HeLa cells. Chimera analysis revealed that two amino acid substitutions (S1259L and I1220M) downstream of the conserved cysteine-rich motif in L1 open reading frame 2 are largely responsible for the observed reduction in L1.2A retrotransposition efficiency. Thus, common L1 alleles can vary widely in their retrotransposition potential. We propose that such allelic heterogeneity can influence the potential L1 mutational load present in an individual genome.\n"
],
"offsets": [
[
0,
1163
]
]
}
] | [
{
"id": "14610717_T1",
"type": "SNP",
"text": [
"S1259L"
],
"offsets": [
[
776,
782
]
],
"normalized": []
},
{
"id": "14610717_T2",
"type": "SNP",
"text": [
"I1220M"
],
"offsets": [
[
787,
793
]
],
"normalized": []
}
] | [] | [] | [] |
152 | 12596792 | [
{
"id": "12596792__text",
"type": "abstract",
"text": [
"Simulation-based P values: response to North et al.\n"
],
"offsets": [
[
0,
52
]
]
}
] | [] | [] | [] | [] |
153 | 12632327 | [
{
"id": "12632327__text",
"type": "abstract",
"text": [
"Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Acrocapitofemoral dysplasia is a recently delineated autosomal recessive skeletal dysplasia, characterized clinically by short stature with short limbs and radiographically by cone-shaped epiphyses, mainly in hands and hips. Genomewide homozygosity mapping in two consanguineous families linked the locus to 2q35-q36 with a maximum two-point LOD score of 8.02 at marker D2S2248. Two recombination events defined the minimal critical region between markers D2S2248 and D2S2151 (3.74 cM). Using a candidate-gene approach, we identified two missense mutations in the amino-terminal signaling domain of the gene encoding Indian hedgehog (IHH). Both affected individuals of family 1 are homozygous for a 137C-->T transition (P46L), and the three patients in family 2 are homozygous for a 569T-->C transition (V190A). The two mutant amino acids are strongly conserved and predicted to be located outside the region where brachydactyly type A-1 mutations are clustered.\n"
],
"offsets": [
[
0,
1104
]
]
}
] | [
{
"id": "12632327_T1",
"type": "Gene",
"text": [
"IHH"
],
"offsets": [
[
24,
27
]
],
"normalized": []
},
{
"id": "12632327_T2",
"type": "Gene",
"text": [
"Indian hedgehog"
],
"offsets": [
[
758,
773
]
],
"normalized": []
},
{
"id": "12632327_T3",
"type": "Gene",
"text": [
"IHH"
],
"offsets": [
[
775,
778
]
],
"normalized": []
},
{
"id": "12632327_T4",
"type": "SNP",
"text": [
"137C-->T"
],
"offsets": [
[
840,
848
]
],
"normalized": []
},
{
"id": "12632327_T5",
"type": "SNP",
"text": [
"P46L"
],
"offsets": [
[
861,
865
]
],
"normalized": []
},
{
"id": "12632327_T6",
"type": "SNP",
"text": [
"569T-->C"
],
"offsets": [
[
924,
932
]
],
"normalized": []
},
{
"id": "12632327_T7",
"type": "SNP",
"text": [
"V190A"
],
"offsets": [
[
945,
950
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12632327_R1",
"type": "Equals",
"arg1_id": "12632327_T2",
"arg2_id": "12632327_T3",
"normalized": []
},
{
"id": "12632327_R2",
"type": "AssociatedTo",
"arg1_id": "12632327_T4",
"arg2_id": "12632327_T3",
"normalized": []
},
{
"id": "12632327_R3",
"type": "AssociatedTo",
"arg1_id": "12632327_T5",
"arg2_id": "12632327_T3",
"normalized": []
},
{
"id": "12632327_R4",
"type": "AssociatedTo",
"arg1_id": "12632327_T6",
"arg2_id": "12632327_T3",
"normalized": []
},
{
"id": "12632327_R5",
"type": "AssociatedTo",
"arg1_id": "12632327_T7",
"arg2_id": "12632327_T3",
"normalized": []
}
] |
154 | 12557124 | [
{
"id": "12557124__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
2340
]
]
}
] | [] | [] | [] | [] |
155 | 12958705 | [
{
"id": "12958705__text",
"type": "abstract",
"text": [
"Genomewide linkage and linkage disequilibrium analyses identify COL6A1, on chromosome 21, as the locus for ossification of the posterior longitudinal ligament of the spine. Ossification of the posterior longitudinal ligament (OPLL) of the spine is a subset of \"bone-forming\" diseases, characterized by ectopic ossification in the spinal ligaments. OPLL is a common disorder among elderly populations in eastern Asia and is the leading cause of spinal myelopathy in Japan. We performed a genomewide linkage study with 142 affected sib pairs, to identify genetic loci related to OPLL. In multipoint linkage analysis using GENEHUNTER-PLUS, evidence of linkage to OPLL was detected on chromosomes 1p, 6p, 11q, 14q, 16q, and 21q. The best evidence of linkage was detected near D21S1903 on chromosome 21q22.3 (maximum Zlr=3.97); therefore, the linkage region was extensively investigated for linkage disequilibrium with single-nucleotide polymorphisms (SNPs) covering 20 Mb. One hundred fifty positional candidate genes lie in the region, and 600 gene-based SNPs were genotyped. There were positive allelic associations with seven genes (P<.01) in 280 patients and 210 controls, and four of the seven genes were clustered within a region of 750 kb, approximately 1.2 Mb telomeric to D21S1903. Extensive linkage disequilibrium and association studies of the four genes indicated that SNPs in the collagen 6A1 gene (COL6A1) were strongly associated with OPLL (P=.000003 for the SNP in intron 32 [-29]). Haplotype analysis with three SNPs in COL6A1 gave a single-point P value of.0000007. Identification of the locus of susceptibility to OPLL by genomewide linkage and linkage disequilibrium studies permits us to investigate the pathogenesis of the disease, which may lead to the development of novel therapeutic tools.\n"
],
"offsets": [
[
0,
1812
]
]
}
] | [
{
"id": "12958705_T1",
"type": "Gene",
"text": [
"COL6A1"
],
"offsets": [
[
64,
70
]
],
"normalized": []
},
{
"id": "12958705_T2",
"type": "Gene",
"text": [
"COL6A1"
],
"offsets": [
[
1408,
1414
]
],
"normalized": []
},
{
"id": "12958705_T3",
"type": "Gene",
"text": [
"collagen 6A1"
],
"offsets": [
[
1389,
1401
]
],
"normalized": []
},
{
"id": "12958705_T4",
"type": "Gene",
"text": [
"COL6A1"
],
"offsets": [
[
1533,
1539
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12958705_R1",
"type": "Equals",
"arg1_id": "12958705_T3",
"arg2_id": "12958705_T2",
"normalized": []
}
] |
156 | 12474144 | [
{
"id": "12474144__text",
"type": "abstract",
"text": [
"Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.\n"
],
"offsets": [
[
0,
1575
]
]
}
] | [
{
"id": "12474144_T1",
"type": "Gene",
"text": [
"dysbindin"
],
"offsets": [
[
214,
223
]
],
"normalized": []
},
{
"id": "12474144_T2",
"type": "Gene",
"text": [
"dysbindin"
],
"offsets": [
[
84,
93
]
],
"normalized": []
}
] | [] | [] | [] |
157 | 14505274 | [
{
"id": "14505274__text",
"type": "abstract",
"text": [
"An Alu transposition model for the origin and expansion of human segmental duplications. Relative to genomes of other sequenced organisms, the human genome appears particularly enriched for large, highly homologous segmental duplications (> or =90% sequence identity and > or =10 kbp in length). The molecular basis for this enrichment is unknown. We sought to gain insight into the mechanism of origin, by systematically examining sequence features at the junctions of duplications. We analyzed 9,464 junctions within regions of high-quality finished sequence from a genomewide set of 2,366 duplication alignments. We observed a highly significant (P<.0001) enrichment of Alu short interspersed element (SINE) sequences near or within the junction. Twenty-seven percent of all segmental duplications terminated within an Alu repeat. The Alu junction enrichment was most pronounced for interspersed segmental duplications separated by > or =1 Mb of intervening sequence. Alu elements at the junctions showed higher levels of divergence, consistent with Alu-Alu-mediated recombination events. When we classified Alu elements into major subfamilies, younger elements (AluY and AluS) accounted for the enrichment, whereas the oldest primate family (AluJ) showed no enrichment. We propose that the primate-specific burst of Alu retroposition activity (which occurred 35-40 million years ago) sensitized the ancestral human genome for Alu-Alu-mediated recombination events, which, in turn, initiated the expansion of gene-rich segmental duplications and their subsequent role in nonallelic homologous recombination.\n"
],
"offsets": [
[
0,
1611
]
]
}
] | [] | [] | [] | [] |
158 | 12489041 | [
{
"id": "12489041__text",
"type": "abstract",
"text": [
"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 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.\n"
],
"offsets": [
[
0,
1265
]
]
}
] | [
{
"id": "12489041_T1",
"type": "Gene",
"text": [
"cytochrome oxidase subunit III"
],
"offsets": [
[
384,
414
]
],
"normalized": []
},
{
"id": "12489041_T2",
"type": "Gene",
"text": [
"HVR1"
],
"offsets": [
[
374,
378
]
],
"normalized": []
},
{
"id": "12489041_T3",
"type": "Gene",
"text": [
"human hypervariable region 1"
],
"offsets": [
[
344,
372
]
],
"normalized": []
},
{
"id": "12489041_T4",
"type": "Gene",
"text": [
"HVR1"
],
"offsets": [
[
535,
539
]
],
"normalized": []
},
{
"id": "12489041_T5",
"type": "Gene",
"text": [
"HVR1"
],
"offsets": [
[
623,
627
]
],
"normalized": []
},
{
"id": "12489041_T6",
"type": "Gene",
"text": [
"HVR1"
],
"offsets": [
[
826,
830
]
],
"normalized": []
},
{
"id": "12489041_T7",
"type": "Gene",
"text": [
"HVR1"
],
"offsets": [
[
1004,
1008
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12489041_R1",
"type": "Equals",
"arg1_id": "12489041_T3",
"arg2_id": "12489041_T2",
"normalized": []
}
] |
159 | 12970847 | [
{
"id": "12970847__text",
"type": "abstract",
"text": [
"Recent advances in human quantitative-trait-locus mapping: comparison of methods for selected sibling pairs. During the past few years, there has been a great deal of new work on methods for mapping quantitative-trait loci by use of sibling pairs and sibships. There are several new methods based on linear regression, as well as several more that are based on score statistics. In theory, most of the new methods should be relatively robust to violations of distributional assumptions and to selected sampling, but, in practice, there has been little evaluation of how the methods perform on selected samples. We survey most of the new regression-based statistics and score statistics and propose a few minor variations on the score statistics. We use simulation to evaluate the type I error and the power of all of the statistics, considering (a) population samples of sibling pairs and (b) sibling pairs ascertained on the basis of at least one sibling with a trait value in the top 10% of the distribution. Most of the statistics have correct type I error for selected samples. The statistics proposed by Xu et al. and by Sham and Purcell are generally the most powerful, along with one of our score statistic variants. Even among the methods that are most powerful for \"nice\" data, some are more robust than others to non-Gaussian trait models and/or misspecified trait parameters.\n"
],
"offsets": [
[
0,
1387
]
]
}
] | [] | [] | [] | [] |
160 | 10053017 | [
{
"id": "10053017__text",
"type": "abstract",
"text": [
"Ancestral Asian source(s) of new world Y-chromosome founder haplotypes. Haplotypes constructed from Y-chromosome markers were used to trace the origins of Native Americans. Our sample consisted of 2,198 males from 60 global populations, including 19 Native American and 15 indigenous North Asian groups. A set of 12 biallelic polymorphisms gave rise to 14 unique Y-chromosome haplotypes that were unevenly distributed among the populations. Combining multiallelic variation at two Y-linked microsatellites (DYS19 and DXYS156Y) with the unique haplotypes results in a total of 95 combination haplotypes. Contra previous findings based on Y- chromosome data, our new results suggest the possibility of more than one Native American paternal founder haplotype. We postulate that, of the nine unique haplotypes found in Native Americans, haplotypes 1C and 1F are the best candidates for major New World founder haplotypes, whereas haplotypes 1B, 1I, and 1U may either be founder haplotypes and/or have arrived in the New World via recent admixture. Two of the other four haplotypes (YAP+ haplotypes 4 and 5) are probably present because of post-Columbian admixture, whereas haplotype 1G may have originated in the New World, and the Old World source of the final New World haplotype (1D) remains unresolved. The contrasting distribution patterns of the two major candidate founder haplotypes in Asia and the New World, as well as the results of a nested cladistic analysis, suggest the possibility of more than one paternal migration from the general region of Lake Baikal to the Americas.\n"
],
"offsets": [
[
0,
1586
]
]
}
] | [
{
"id": "10053017_T1",
"type": "Gene",
"text": [
"YAP+"
],
"offsets": [
[
1079,
1083
]
],
"normalized": []
}
] | [] | [] | [] |
161 | 10090909 | [
{
"id": "10090909__text",
"type": "abstract",
"text": [
"A mutation (2314delG) in the Usher syndrome type IIA gene: high prevalence and phenotypic variation.\n"
],
"offsets": [
[
0,
101
]
]
}
] | [
{
"id": "10090909_T1",
"type": "SNP",
"text": [
"2314delG"
],
"offsets": [
[
12,
20
]
],
"normalized": []
},
{
"id": "10090909_T2",
"type": "Gene",
"text": [
"Usher syndrome type IIA gene"
],
"offsets": [
[
29,
57
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10090909_R1",
"type": "AssociatedTo",
"arg1_id": "10090909_T1",
"arg2_id": "10090909_T2",
"normalized": []
}
] |
162 | 10577916 | [
{
"id": "10577916__text",
"type": "abstract",
"text": [
"Variation in short tandem repeats is deeply structured by genetic background on the human Y chromosome. Eleven biallelic polymorphisms and seven short-tandem-repeat (STR) loci mapping on the nonrecombining portion of the human Y chromosome have been typed in men from northwestern Africa. Analysis of the biallelic markers, which represent probable unique events in human evolution, allowed us to characterize the stable backgrounds or haplogroups of Y chromosomes that prevail in this geographic region. Variation in the more rapidly mutating genetic markers (STRs) has been used both to estimate the time to the most recent common ancestor for STR variability within these stable backgrounds and to explore whether STR differentiation among haplogroups still retains information about their phylogeny. When analysis of molecular variance was used to study the apportionment of STR variation among both genetic backgrounds (i.e., those defined by haplogroups) and population backgrounds, we found STR variability to be clearly structured by haplogroups. More than 80% of the genetic variance was found among haplogroups, whereas only 3.72% of the genetic variation could be attributed to differences among populations-that is, genetic variability appears to be much more structured by lineage than by population. This was confirmed when two population samples from the Iberian Peninsula were added to the analysis. The deep structure of the genetic variation in old genealogical units (haplogroups) challenges a population-based perspective in the comprehension of human genome diversity. A population may be better understood as an association of lineages from a deep and population-independent gene genealogy, rather than as a complete evolutionary unit.\n"
],
"offsets": [
[
0,
1758
]
]
}
] | [] | [] | [] | [] |
163 | 10521296 | [
{
"id": "10521296__text",
"type": "abstract",
"text": [
"The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events. Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations-Ala797Thr in the beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.\n"
],
"offsets": [
[
0,
1813
]
]
}
] | [
{
"id": "10521296_T1",
"type": "SNP",
"text": [
"Ala797Thr"
],
"offsets": [
[
818,
827
]
],
"normalized": []
},
{
"id": "10521296_T2",
"type": "Gene",
"text": [
"betaMHC"
],
"offsets": [
[
865,
872
]
],
"normalized": []
},
{
"id": "10521296_T3",
"type": "SNP",
"text": [
"Arg92Trp"
],
"offsets": [
[
875,
883
]
],
"normalized": []
},
{
"id": "10521296_T4",
"type": "Gene",
"text": [
"cTnT"
],
"offsets": [
[
916,
920
]
],
"normalized": []
},
{
"id": "10521296_T5",
"type": "SNP",
"text": [
"Arg645His"
],
"offsets": [
[
927,
936
]
],
"normalized": []
},
{
"id": "10521296_T6",
"type": "Gene",
"text": [
"MyBPC"
],
"offsets": [
[
975,
980
]
],
"normalized": []
},
{
"id": "10521296_T7",
"type": "Gene",
"text": [
"betaMHC"
],
"offsets": [
[
1001,
1008
]
],
"normalized": []
},
{
"id": "10521296_T8",
"type": "SNP",
"text": [
"Arg403Trp"
],
"offsets": [
[
1020,
1029
]
],
"normalized": []
},
{
"id": "10521296_T9",
"type": "SNP",
"text": [
"Arg249Gln"
],
"offsets": [
[
1034,
1043
]
],
"normalized": []
},
{
"id": "10521296_T10",
"type": "SNP",
"text": [
"Gln499Lys"
],
"offsets": [
[
1094,
1103
]
],
"normalized": []
},
{
"id": "10521296_T11",
"type": "Gene",
"text": [
"betaMHC"
],
"offsets": [
[
1107,
1114
]
],
"normalized": []
},
{
"id": "10521296_T12",
"type": "SNP",
"text": [
"Val896Met"
],
"offsets": [
[
1119,
1128
]
],
"normalized": []
},
{
"id": "10521296_T13",
"type": "SNP",
"text": [
"Deltac756"
],
"offsets": [
[
1133,
1142
]
],
"normalized": []
},
{
"id": "10521296_T14",
"type": "Gene",
"text": [
"MyBPC-and"
],
"offsets": [
[
1146,
1155
]
],
"normalized": []
},
{
"id": "10521296_T15",
"type": "Gene",
"text": [
"beta-myosin heavy-chain gene"
],
"offsets": [
[
835,
863
]
],
"normalized": []
},
{
"id": "10521296_T16",
"type": "Gene",
"text": [
"cardiac troponin T gene"
],
"offsets": [
[
891,
914
]
],
"normalized": []
},
{
"id": "10521296_T17",
"type": "Gene",
"text": [
"myosin-binding protein C gene"
],
"offsets": [
[
944,
973
]
],
"normalized": []
},
{
"id": "10521296_T18",
"type": "Gene",
"text": [
"betaMHC"
],
"offsets": [
[
1171,
1178
]
],
"normalized": []
},
{
"id": "10521296_T19",
"type": "SNP",
"text": [
"Arg719Gln"
],
"offsets": [
[
1179,
1188
]
],
"normalized": []
},
{
"id": "10521296_T20",
"type": "Gene",
"text": [
"betaMHC"
],
"offsets": [
[
1324,
1331
]
],
"normalized": []
},
{
"id": "10521296_T21",
"type": "SNP",
"text": [
"Arg403Trp"
],
"offsets": [
[
1332,
1341
]
],
"normalized": []
},
{
"id": "10521296_T22",
"type": "SNP",
"text": [
"Ala797Thr"
],
"offsets": [
[
1346,
1355
]
],
"normalized": []
},
{
"id": "10521296_T24",
"type": "Gene",
"text": [
"betaMHC"
],
"offsets": [
[
1603,
1610
]
],
"normalized": []
},
{
"id": "10521296_T23",
"type": "SNP",
"text": [
"Arg92Trp"
],
"offsets": [
[
1365,
1373
]
],
"normalized": []
},
{
"id": "10521296_T25",
"type": "SNP",
"text": [
"Arg92Trp"
],
"offsets": [
[
1794,
1802
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10521296_R1",
"type": "Equals",
"arg1_id": "10521296_T15",
"arg2_id": "10521296_T2",
"normalized": []
},
{
"id": "10521296_R2",
"type": "AssociatedTo",
"arg1_id": "10521296_T1",
"arg2_id": "10521296_T15",
"normalized": []
},
{
"id": "10521296_R3",
"type": "AssociatedTo",
"arg1_id": "10521296_T1",
"arg2_id": "10521296_T2",
"normalized": []
},
{
"id": "10521296_R4",
"type": "Equals",
"arg1_id": "10521296_T16",
"arg2_id": "10521296_T4",
"normalized": []
},
{
"id": "10521296_R5",
"type": "AssociatedTo",
"arg1_id": "10521296_T3",
"arg2_id": "10521296_T16",
"normalized": []
},
{
"id": "10521296_R6",
"type": "AssociatedTo",
"arg1_id": "10521296_T3",
"arg2_id": "10521296_T4",
"normalized": []
},
{
"id": "10521296_R7",
"type": "Equals",
"arg1_id": "10521296_T17",
"arg2_id": "10521296_T6",
"normalized": []
},
{
"id": "10521296_R8",
"type": "AssociatedTo",
"arg1_id": "10521296_T5",
"arg2_id": "10521296_T17",
"normalized": []
},
{
"id": "10521296_R9",
"type": "AssociatedTo",
"arg1_id": "10521296_T5",
"arg2_id": "10521296_T6",
"normalized": []
},
{
"id": "10521296_R10",
"type": "AssociatedTo",
"arg1_id": "10521296_T8",
"arg2_id": "10521296_T7",
"normalized": []
},
{
"id": "10521296_R11",
"type": "AssociatedTo",
"arg1_id": "10521296_T9",
"arg2_id": "10521296_T7",
"normalized": []
},
{
"id": "10521296_R12",
"type": "AssociatedTo",
"arg1_id": "10521296_T10",
"arg2_id": "10521296_T11",
"normalized": []
},
{
"id": "10521296_R13",
"type": "AssociatedTo",
"arg1_id": "10521296_T13",
"arg2_id": "10521296_T14",
"normalized": []
},
{
"id": "10521296_R14",
"type": "AssociatedTo",
"arg1_id": "10521296_T12",
"arg2_id": "10521296_T14",
"normalized": []
},
{
"id": "10521296_R15",
"type": "AssociatedTo",
"arg1_id": "10521296_T19",
"arg2_id": "10521296_T18",
"normalized": []
},
{
"id": "10521296_R16",
"type": "AssociatedTo",
"arg1_id": "10521296_T21",
"arg2_id": "10521296_T20",
"normalized": []
},
{
"id": "10521296_R17",
"type": "AssociatedTo",
"arg1_id": "10521296_T22",
"arg2_id": "10521296_T20",
"normalized": []
},
{
"id": "10521296_R18",
"type": "AssociatedTo",
"arg1_id": "10521296_T23",
"arg2_id": "10521296_T20",
"normalized": []
},
{
"id": "10521296_R19",
"type": "AssociatedTo",
"arg1_id": "10521296_T25",
"arg2_id": "10521296_T24",
"normalized": []
}
] |
164 | 10486328 | [
{
"id": "10486328__text",
"type": "abstract",
"text": [
"Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. Hydrolethalus syndrome is a recessively inherited lethal malformation syndrome characterized by hydrocephaly with absent midline structures of the brain, micrognathia, polydactyly, and several other abnormalities, mostly in the midline structures. Hydrolethalus syndrome was described in 1981 in Finland, where the incidence is 1:20,000. Only a few cases have been reported elsewhere, and the pathogenesis has remained unknown. Here we report the assignment of the hydrolethalus syndrome locus to chromosome 11q23-25 in Finnish families. The initial genome scan was performed using DNA samples from only 15 affected individuals. In the next step, the hydrolethalus syndrome locus was assigned to an 8.5-cM interval between markers D11S4144 and D11S1351 by linkage analysis in eight families. Finally, the critical locus could be restricted by linkage disequilibrium and haplotype analyses to a 0.5-1-cM region between markers D11S933 and D11S934. Genealogical studies performed in 40 families affected by hydrolethalus revealed no regional clustering, suggesting a relatively early introduction of the disease mutation into the Finnish population and the spreading of the mutation with the inhabitation of the late-settlement area.\n"
],
"offsets": [
[
0,
1326
]
]
}
] | [] | [] | [] | [] |
165 | 9973270 | [
{
"id": "9973270__text",
"type": "abstract",
"text": [
"Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold.\n"
],
"offsets": [
[
0,
94
]
]
}
] | [] | [] | [] | [] |
166 | 10330344 | [
{
"id": "10330344__text",
"type": "abstract",
"text": [
"Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups.\n"
],
"offsets": [
[
0,
1605
]
]
}
] | [
{
"id": "10330344_T1",
"type": "Gene",
"text": [
"TRKA"
],
"offsets": [
[
73,
77
]
],
"normalized": []
},
{
"id": "10330344_T2",
"type": "Gene",
"text": [
"NTRK1"
],
"offsets": [
[
79,
84
]
],
"normalized": []
},
{
"id": "10330344_T3",
"type": "Gene",
"text": [
"TRKA"
],
"offsets": [
[
396,
400
]
],
"normalized": []
},
{
"id": "10330344_T4",
"type": "Gene",
"text": [
"TRKA"
],
"offsets": [
[
776,
780
]
],
"normalized": []
},
{
"id": "10330344_T5",
"type": "Gene",
"text": [
"TRKA"
],
"offsets": [
[
651,
655
]
],
"normalized": []
},
{
"id": "10330344_T6",
"type": "Gene",
"text": [
"TRKA"
],
"offsets": [
[
885,
889
]
],
"normalized": []
},
{
"id": "10330344_T7",
"type": "SNP",
"text": [
"Arg85Ser"
],
"offsets": [
[
1294,
1302
]
],
"normalized": []
},
{
"id": "10330344_T9",
"type": "Gene",
"text": [
"TRKA"
],
"offsets": [
[
1555,
1559
]
],
"normalized": []
},
{
"id": "10330344_T8",
"type": "SNP",
"text": [
"His598Tyr"
],
"offsets": [
[
1310,
1319
]
],
"normalized": []
},
{
"id": "10330344_T10",
"type": "SNP",
"text": [
"Gly607Val"
],
"offsets": [
[
1320,
1329
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10330344_R1",
"type": "Equals",
"arg1_id": "10330344_T1",
"arg2_id": "10330344_T2",
"normalized": []
}
] |
167 | 10441582 | [
{
"id": "10441582__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1303
]
]
}
] | [] | [] | [] | [] |
168 | 10417286 | [
{
"id": "10417286__text",
"type": "abstract",
"text": [
"Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1. van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.\n"
],
"offsets": [
[
0,
1422
]
]
}
] | [
{
"id": "10417286_T1",
"type": "Gene",
"text": [
"VWS,"
],
"offsets": [
[
373,
377
]
],
"normalized": []
},
{
"id": "10417286_T2",
"type": "Gene",
"text": [
"VWS"
],
"offsets": [
[
952,
955
]
],
"normalized": []
}
] | [] | [] | [] |
169 | 9915936 | [
{
"id": "9915936__text",
"type": "abstract",
"text": [
"1998 ASHG presidential address. Making genomic medicine a reality.\n"
],
"offsets": [
[
0,
67
]
]
}
] | [] | [] | [] | [] |
170 | 10205286 | [
{
"id": "10205286__text",
"type": "abstract",
"text": [
"Genomewide Transmission/Disequilibrium testing: a correction.\n"
],
"offsets": [
[
0,
62
]
]
}
] | [] | [] | [] | [] |
171 | 9973271 | [
{
"id": "9973271__text",
"type": "abstract",
"text": [
"Biological implications of the DNA structures associated with disease-causing triplet repeats.\n"
],
"offsets": [
[
0,
95
]
]
}
] | [] | [] | [] | [] |
172 | 9973288 | [
{
"id": "9973288__text",
"type": "abstract",
"text": [
"Hyperparathyroidism-jaw tumor syndrome: the HRPT2 locus is within a 0.7-cM region on chromosome 1q. Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease characterized by the development of multiple parathyroid adenomas and multiple fibro-osseous tumors of the maxilla and mandible. Some families have had affected members with involvement of the kidneys, variously reported as Wilms tumors, nephroblastomas, and hamartomas. The HPT-JT gene (HRPT2) maps to chromosome 1q25-q31. We describe further investigation of two HPT-JT families (K3304 and K3349) identified through the literature. These two expanded families and two previously reported families were investigated jointly for linkage with 21 new, closely linked markers. Multipoint linkage analysis resulted in a maximum LOD score of 7.83 (at recombination fraction 0) for markers D1S2848-D1S191. Recombination events in these families reduced the HRPT2 region to approximately 14.7 cM. In addition, two of these four study families (i.e., K3304 and K11687) share a 2.2-cM length of their (expanded) affected haplotype, indicating a possible common origin. Combining the linkage data and shared-haplotype data, we propose a 0.7-cM candidate region for HRPT2.\n"
],
"offsets": [
[
0,
1243
]
]
}
] | [
{
"id": "9973288_T1",
"type": "Gene",
"text": [
"HRPT2"
],
"offsets": [
[
44,
49
]
],
"normalized": []
},
{
"id": "9973288_T3",
"type": "Gene",
"text": [
"(HRPT2)"
],
"offsets": [
[
468,
475
]
],
"normalized": []
},
{
"id": "9973288_T4",
"type": "Gene",
"text": [
"HRPT2"
],
"offsets": [
[
932,
937
]
],
"normalized": []
},
{
"id": "9973288_T5",
"type": "Gene",
"text": [
"HRPT2."
],
"offsets": [
[
1236,
1242
]
],
"normalized": []
}
] | [] | [] | [] |
173 | 10577941 | [
{
"id": "10577941__text",
"type": "abstract",
"text": [
"Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia.\n"
],
"offsets": [
[
0,
142
]
]
}
] | [
{
"id": "10577941_T1",
"type": "SNP",
"text": [
"A1555G"
],
"offsets": [
[
94,
100
]
],
"normalized": []
}
] | [] | [] | [] |
174 | 9915955 | [
{
"id": "9915955__text",
"type": "abstract",
"text": [
"Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.\n"
],
"offsets": [
[
0,
1187
]
]
}
] | [] | [] | [] | [] |
175 | 9915968 | [
{
"id": "9915968__text",
"type": "abstract",
"text": [
"The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease.\n"
],
"offsets": [
[
0,
89
]
]
}
] | [
{
"id": "9915968_T1",
"type": "SNP",
"text": [
"Glu318Gly"
],
"offsets": [
[
4,
13
]
],
"normalized": []
},
{
"id": "9915968_T2",
"type": "Gene",
"text": [
"presenilin 1"
],
"offsets": [
[
30,
42
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9915968_R1",
"type": "AssociatedTo",
"arg1_id": "9915968_T1",
"arg2_id": "9915968_T2",
"normalized": []
}
] |
176 | 10090915 | [
{
"id": "10090915__text",
"type": "abstract",
"text": [
"Prevalence of Bloom syndrome heterozygotes among Ashkenazi Jews.\n"
],
"offsets": [
[
0,
65
]
]
}
] | [] | [] | [] | [] |
177 | 10521316 | [
{
"id": "10521316__text",
"type": "abstract",
"text": [
"Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15.\n"
],
"offsets": [
[
0,
90
]
]
}
] | [
{
"id": "10521316_T1",
"type": "Gene",
"text": [
"MCPH4"
],
"offsets": [
[
66,
71
]
],
"normalized": []
}
] | [] | [] | [] |
178 | 10521310 | [
{
"id": "10521310__text",
"type": "abstract",
"text": [
"A complete genome screen in sib pairs affected by Gilles de la Tourette syndrome. The Tourette Syndrome Association International Consortium for Genetics. Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by waxing and waning multiple motor and phonic tics with a complex mode of inheritance. Previous attempts, which used large multigenerational families to localize susceptibility loci, have been unsuccessful. In this report, the results of the first systematic genome scan, using 76 affected-sib-pair families with a total of 110 sib pairs, are summarized. While no results reached acceptable statistical significance, the multipoint maximum-likelihood scores (MLS) for two regions (4q and 8p) were suggestive (MLS > 2.0). Four additional genomic regions also gave multipoint MLS scores between 1.0 and 2.0.\n"
],
"offsets": [
[
0,
838
]
]
}
] | [] | [] | [] | [] |
179 | 10486315 | [
{
"id": "10486315__text",
"type": "abstract",
"text": [
"Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level. The factors influencing the tissue-specific pattern of somatic mosaicism in CAG-repeat diseases have not yet been fully resolved. We performed a detailed analysis of the degree of somatic mosaicism in various tissues from 20 patients with spinal and bulbar muscular atrophy (SBMA), including 4 who were deceased. The most outstanding feature was the prominent somatic mosaicism observed in the cardiac and skeletal muscles, composed predominantly of postmitotic cells, and in the skin, prostate, and testis. The CNS tissues, liver, and spleen showed the least mosaicism. The tissue distribution of somatic mosaicism in patients with SBMA was markedly different from that in patients with Huntington disease (HD) and from that in patients with dentatorubral-pallidoluysian atrophy (DRPLA). The degree of somatic mosaicism correlated with the CAG-repeat number but not with age at examination. Furthermore, tissues with a higher mosaicism level corresponded well to those with a higher expression level of androgen receptor protein. The tissue-specific pattern of somatic mosaicism related not only to cell composition with different cell turnover rates but to repeat size and gene expression levels, and postnatal cell division is unlikely to be a major cause of somatic mosaicism probably because of the relative stability of CAG repeat in SBMA.\n"
],
"offsets": [
[
0,
1498
]
]
}
] | [] | [] | [] | [] |
180 | 20529654 | [
{
"id": "20529654__text",
"type": "abstract",
"text": [
"ASHG Awards and Addresses. 2009 William Allan Award address: Life in the sandbox: unfinished business.\n"
],
"offsets": [
[
0,
103
]
]
}
] | [] | [] | [] | [] |
181 | 20471002 | [
{
"id": "20471002__text",
"type": "abstract",
"text": [
"Pooled association tests for rare variants in exon-resequencing studies. Deep sequencing will soon generate comprehensive sequence information in large disease samples. Although the power to detect association with an individual rare variant is limited, pooling variants by gene or pathway into a composite test provides an alternative strategy for identifying susceptibility genes. We describe a statistical method for detecting association of multiple rare variants in protein-coding genes with a quantitative or dichotomous trait. The approach is based on the regression of phenotypic values on individuals' genotype scores subject to a variable allele-frequency threshold, incorporating computational predictions of the functional effects of missense variants. Statistical significance is assessed by permutation testing with variable thresholds. We used a rigorous population-genetics simulation framework to evaluate the power of the method, and we applied the method to empirical sequencing data from three disease studies.\n"
],
"offsets": [
[
0,
1031
]
]
}
] | [] | [] | [] | [] |
182 | 20598277 | [
{
"id": "20598277__text",
"type": "abstract",
"text": [
"Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene.\n"
],
"offsets": [
[
0,
1443
]
]
}
] | [
{
"id": "20598277_T1",
"type": "Gene",
"text": [
"FLNA"
],
"offsets": [
[
75,
79
]
],
"normalized": []
},
{
"id": "20598277_T2",
"type": "Gene",
"text": [
"FLNA"
],
"offsets": [
[
420,
424
]
],
"normalized": []
},
{
"id": "20598277_T3",
"type": "SNP",
"text": [
"c.5217G>A"
],
"offsets": [
[
483,
492
]
],
"normalized": []
},
{
"id": "20598277_T4",
"type": "Gene",
"text": [
"FLNA"
],
"offsets": [
[
665,
669
]
],
"normalized": []
},
{
"id": "20598277_T5",
"type": "SNP",
"text": [
"p.Val1724_Thr1739del"
],
"offsets": [
[
1267,
1287
]
],
"normalized": []
},
{
"id": "20598277_T6",
"type": "Gene",
"text": [
"FLNA"
],
"offsets": [
[
1432,
1436
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20598277_R1",
"type": "AssociatedTo",
"arg1_id": "20598277_T3",
"arg2_id": "20598277_T4",
"normalized": []
},
{
"id": "20598277_R2",
"type": "AssociatedTo",
"arg1_id": "20598277_T5",
"arg2_id": "20598277_T6",
"normalized": []
}
] |
183 | 20137772 | [
{
"id": "20137772__text",
"type": "abstract",
"text": [
"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) 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.\n"
],
"offsets": [
[
0,
999
]
]
}
] | [
{
"id": "20137772_T1",
"type": "Gene",
"text": [
"ENPP1"
],
"offsets": [
[
96,
101
]
],
"normalized": []
},
{
"id": "20137772_T2",
"type": "Gene",
"text": [
"PHEX"
],
"offsets": [
[
224,
228
]
],
"normalized": []
},
{
"id": "20137772_T3",
"type": "Gene",
"text": [
"FGF23"
],
"offsets": [
[
230,
235
]
],
"normalized": []
},
{
"id": "20137772_T4",
"type": "Gene",
"text": [
"DMP1"
],
"offsets": [
[
241,
245
]
],
"normalized": []
},
{
"id": "20137772_T5",
"type": "Gene",
"text": [
"ENPP1"
],
"offsets": [
[
467,
472
]
],
"normalized": []
},
{
"id": "20137772_T6",
"type": "Gene",
"text": [
"pyrophosphatase/phosphodiesterase 1"
],
"offsets": [
[
430,
465
]
],
"normalized": []
},
{
"id": "20137772_T7",
"type": "Gene",
"text": [
"ENPP1"
],
"offsets": [
[
580,
585
]
],
"normalized": []
},
{
"id": "20137772_T9",
"type": "Gene",
"text": [
"ENPP1"
],
"offsets": [
[
992,
997
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20137772_R1",
"type": "Equals",
"arg1_id": "20137772_T6",
"arg2_id": "20137772_T5",
"normalized": []
}
] |
184 | 20537299 | [
{
"id": "20537299__text",
"type": "abstract",
"text": [
"Principal-component analysis for assessment of population stratification in mitochondrial medical genetics. Although inherited mitochondrial genetic variation can cause human disease, no validated methods exist for control of confounding due to mitochondrial population stratification (PS). We sought to identify a reliable method for PS assessment in mitochondrial medical genetics. We analyzed mitochondrial SNP data from 1513 European American individuals concomitantly genotyped with the use of a previously validated panel of 144 mitochondrial markers as well as the Affymetrix 6.0 (n = 432), Illumina 610-Quad (n = 458), or Illumina 660 (n = 623) platforms. Additional analyses were performed in 938 participants in the Human Genome Diversity Panel (HGDP) (Illumina 650). We compared the following methods for controlling for PS: haplogroup-stratified analyses, mitochondrial principal-component analysis (PCA), and combined autosomal-mitochondrial PCA. We computed mitochondrial genomic inflation factors (mtGIFs) and test statistics for simulated case-control and continuous phenotypes (10,000 simulations each) with varying degrees of correlation with mitochondrial ancestry. Results were then compared across adjustment methods. We also calculated power for discovery of true associations under each method, using a simulation approach. Mitochondrial PCA recapitulated haplogroup information, but haplogroup-stratified analyses were inferior to mitochondrial PCA in controlling for PS. Correlation between nuclear and mitochondrial principal components (PCs) was very limited. Adjustment for nuclear PCs had no effect on mitochondrial analysis of simulated phenotypes. Mitochondrial PCA performed with the use of data from commercially available genome-wide arrays correlated strongly with PCA performed with the use of an exhaustive mitochondrial marker panel. Finally, we demonstrate, through simulation, no loss in power for detection of true associations with the use of mitochondrial PCA.\n"
],
"offsets": [
[
0,
2004
]
]
}
] | [] | [] | [] | [] |
185 | 20579627 | [
{
"id": "20579627__text",
"type": "abstract",
"text": [
"X-linked cone dystrophy caused by mutation of the red and green cone opsins. X-linked cone and cone-rod dystrophies (XLCOD and XLCORD) are a heterogeneous group of progressive disorders that solely or primarily affect cone photoreceptors. Mutations in exon ORF15 of the RPGR gene are the most common underlying cause. In a previous study, we excluded RPGR exon ORF15 in some families with XLCOD. Here, we report genetic mapping of XLCOD to Xq26.1-qter. A significant LOD score was detected with marker DXS8045 (Z(max) = 2.41 [theta = 0.0]). The disease locus encompasses the cone opsin gene array on Xq28. Analysis of the array revealed a missense mutation (c. 529T>C [p. W177R]) in exon 3 of both the long-wavelength-sensitive (LW, red) and medium-wavelength-sensitive (MW, green) cone opsin genes that segregated with disease. Both exon 3 sequences were identical and were derived from the MW gene as a result of gene conversion. The amino acid W177 is highly conserved in visual and nonvisual opsins across species. We show that W177R in MW opsin and the equivalent W161R mutation in rod opsin result in protein misfolding and retention in the endoplasmic reticulum. We also demonstrate that W177R misfolding, unlike the P23H mutation in rod opsin that causes retinitis pigmentosa, is not rescued by treatment with the pharmacological chaperone 9-cis-retinal. Mutations in the LW/MW cone opsin gene array can, therefore, lead to a spectrum of disease, ranging from color blindness to progressive cone dystrophy (XLCOD5).\n"
],
"offsets": [
[
0,
1524
]
]
}
] | [
{
"id": "20579627_T1",
"type": "Gene",
"text": [
"RPGR"
],
"offsets": [
[
270,
274
]
],
"normalized": []
},
{
"id": "20579627_T2",
"type": "Gene",
"text": [
"RPGR"
],
"offsets": [
[
351,
355
]
],
"normalized": []
},
{
"id": "20579627_T3",
"type": "SNP",
"text": [
"c. 529T>C"
],
"offsets": [
[
658,
667
]
],
"normalized": []
},
{
"id": "20579627_T4",
"type": "SNP",
"text": [
"W177R"
],
"offsets": [
[
1032,
1037
]
],
"normalized": []
},
{
"id": "20579627_T5",
"type": "SNP",
"text": [
"W161R"
],
"offsets": [
[
1069,
1074
]
],
"normalized": []
},
{
"id": "20579627_T6",
"type": "SNP",
"text": [
"W177R"
],
"offsets": [
[
1195,
1200
]
],
"normalized": []
},
{
"id": "20579627_T7",
"type": "SNP",
"text": [
"P23H"
],
"offsets": [
[
1224,
1228
]
],
"normalized": []
},
{
"id": "20579627_T8",
"type": "SNP",
"text": [
"p. W177R"
],
"offsets": [
[
669,
677
]
],
"normalized": []
},
{
"id": "20579627_T9",
"type": "Gene",
"text": [
"LW"
],
"offsets": [
[
729,
731
]
],
"normalized": []
},
{
"id": "20579627_T12",
"type": "SNP",
"text": [
"LW"
],
"offsets": [
[
729,
731
]
],
"normalized": []
}
] | [] | [] | [] |
186 | 20887961 | [
{
"id": "20887961__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1686
]
]
}
] | [
{
"id": "20887961_T1",
"type": "Gene",
"text": [
"SCARF2"
],
"offsets": [
[
13,
19
]
],
"normalized": []
},
{
"id": "20887961_T2",
"type": "Gene",
"text": [
"SCARF2"
],
"offsets": [
[
798,
804
]
],
"normalized": []
},
{
"id": "20887961_T3",
"type": "SNP",
"text": [
"c.773G>A"
],
"offsets": [
[
969,
977
]
],
"normalized": []
},
{
"id": "20887961_T4",
"type": "SNP",
"text": [
"p.C258Y"
],
"offsets": [
[
979,
986
]
],
"normalized": []
},
{
"id": "20887961_T5",
"type": "SNP",
"text": [
"c.1328_1329delTG"
],
"offsets": [
[
1066,
1082
]
],
"normalized": []
},
{
"id": "20887961_T6",
"type": "SNP",
"text": [
"p.V443DfsX83"
],
"offsets": [
[
1084,
1096
]
],
"normalized": []
},
{
"id": "20887961_T7",
"type": "Gene",
"text": [
"SCARF2"
],
"offsets": [
[
1226,
1232
]
],
"normalized": []
},
{
"id": "20887961_T8",
"type": "Gene",
"text": [
"SCARF2"
],
"offsets": [
[
1269,
1275
]
],
"normalized": []
},
{
"id": "20887961_T9",
"type": "Gene",
"text": [
"SCARF2"
],
"offsets": [
[
1528,
1534
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20887961_R1",
"type": "AssociatedTo",
"arg1_id": "20887961_T3",
"arg2_id": "20887961_T2",
"normalized": []
},
{
"id": "20887961_R2",
"type": "AssociatedTo",
"arg1_id": "20887961_T4",
"arg2_id": "20887961_T2",
"normalized": []
},
{
"id": "20887961_R3",
"type": "AssociatedTo",
"arg1_id": "20887961_T5",
"arg2_id": "20887961_T2",
"normalized": []
},
{
"id": "20887961_R4",
"type": "AssociatedTo",
"arg1_id": "20887961_T6",
"arg2_id": "20887961_T2",
"normalized": []
}
] |
187 | 21035103 | [
{
"id": "21035103__text",
"type": "abstract",
"text": [
"Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene. Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.\n"
],
"offsets": [
[
0,
1376
]
]
}
] | [
{
"id": "21035103_T1",
"type": "Gene",
"text": [
"COL11A1"
],
"offsets": [
[
50,
57
]
],
"normalized": []
},
{
"id": "21035103_T2",
"type": "Gene",
"text": [
"COL11A1"
],
"offsets": [
[
638,
645
]
],
"normalized": []
},
{
"id": "21035103_T3",
"type": "Gene",
"text": [
"COL11A1"
],
"offsets": [
[
743,
750
]
],
"normalized": []
},
{
"id": "21035103_T4",
"type": "Gene",
"text": [
"COL11A1"
],
"offsets": [
[
1170,
1177
]
],
"normalized": []
},
{
"id": "21035103_T5",
"type": "Gene",
"text": [
"COL11A1"
],
"offsets": [
[
1258,
1265
]
],
"normalized": []
}
] | [] | [] | [] |
188 | 20466092 | [
{
"id": "20466092__text",
"type": "abstract",
"text": [
"The number of markers in the HapMap project: some notes on chi-square and exact tests for Hardy-Weinberg equilibrium.\n"
],
"offsets": [
[
0,
118
]
]
}
] | [] | [] | [] | [] |
189 | 20602914 | [
{
"id": "20602914__text",
"type": "abstract",
"text": [
"Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss.\n"
],
"offsets": [
[
0,
1215
]
]
}
] | [
{
"id": "20602914_T1",
"type": "Gene",
"text": [
"GPSM2"
],
"offsets": [
[
95,
100
]
],
"normalized": []
},
{
"id": "20602914_T2",
"type": "Gene",
"text": [
"G protein signaling modulator"
],
"offsets": [
[
782,
811
]
],
"normalized": []
},
{
"id": "20602914_T3",
"type": "Gene",
"text": [
"GPSM2"
],
"offsets": [
[
812,
817
]
],
"normalized": []
},
{
"id": "20602914_T4",
"type": "Gene",
"text": [
"GPSM2"
],
"offsets": [
[
929,
934
]
],
"normalized": []
},
{
"id": "20602914_T5",
"type": "Gene",
"text": [
"GPSM2"
],
"offsets": [
[
1079,
1084
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20602914_R1",
"type": "Equals",
"arg1_id": "20602914_T2",
"arg2_id": "20602914_T3",
"normalized": []
}
] |
190 | 20826270 | [
{
"id": "20826270__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1301
]
]
}
] | [
{
"id": "20826270_T1",
"type": "Gene",
"text": [
"PTPN14"
],
"offsets": [
[
29,
35
]
],
"normalized": []
},
{
"id": "20826270_T2",
"type": "Gene",
"text": [
"Protein tyrosine phosphatase"
],
"offsets": [
[
0,
28
]
],
"normalized": []
},
{
"id": "20826270_T3",
"type": "Gene",
"text": [
"PTPN14"
],
"offsets": [
[
719,
725
]
],
"normalized": []
},
{
"id": "20826270_T4",
"type": "Gene",
"text": [
"PTPN14"
],
"offsets": [
[
796,
802
]
],
"normalized": []
},
{
"id": "20826270_T5",
"type": "Gene",
"text": [
"Ptpn14"
],
"offsets": [
[
858,
864
]
],
"normalized": []
},
{
"id": "20826270_T6",
"type": "Gene",
"text": [
"PTPN14"
],
"offsets": [
[
997,
1003
]
],
"normalized": []
},
{
"id": "20826270_T7",
"type": "Gene",
"text": [
"vascular endothelial growth factor receptor 3"
],
"offsets": [
[
1012,
1057
]
],
"normalized": []
},
{
"id": "20826270_T8",
"type": "Gene",
"text": [
"VEGFR3"
],
"offsets": [
[
1059,
1065
]
],
"normalized": []
},
{
"id": "20826270_T9",
"type": "Gene",
"text": [
"PTPN14"
],
"offsets": [
[
1182,
1188
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20826270_R1",
"type": "Equals",
"arg1_id": "20826270_T2",
"arg2_id": "20826270_T1",
"normalized": []
},
{
"id": "20826270_R2",
"type": "Equals",
"arg1_id": "20826270_T7",
"arg2_id": "20826270_T8",
"normalized": []
}
] |
191 | 20817137 | [
{
"id": "20817137__text",
"type": "abstract",
"text": [
"Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder.\n"
],
"offsets": [
[
0,
902
]
]
}
] | [
{
"id": "20817137_T1",
"type": "Gene",
"text": [
"WDR35"
],
"offsets": [
[
28,
33
]
],
"normalized": []
},
{
"id": "20817137_T2",
"type": "Gene",
"text": [
"WDR35"
],
"offsets": [
[
358,
363
]
],
"normalized": []
},
{
"id": "20817137_T3",
"type": "Gene",
"text": [
"WDR35"
],
"offsets": [
[
613,
618
]
],
"normalized": []
},
{
"id": "20817137_T4",
"type": "Gene",
"text": [
"WDR35"
],
"offsets": [
[
702,
707
]
],
"normalized": []
},
{
"id": "20817137_T5",
"type": "Gene",
"text": [
"TULP4"
],
"offsets": [
[
725,
730
]
],
"normalized": []
}
] | [] | [] | [] |
192 | 21129725 | [
{
"id": "21129725__text",
"type": "abstract",
"text": [
"Replication strategies for rare variant complex trait association studies via next-generation sequencing. There is solid evidence that complex traits can be caused by rare variants. Next-generation sequencing technologies are powerful tools for mapping rare variants. Confirmation of significant findings in stage 1 through replication in an independent stage 2 sample is necessary for association studies. For gene-based mapping of rare variants, two replication strategies are possible: (1) variant-based replication, wherein only variants from nucleotide sites uncovered in stage 1 are genotyped and followed-up and (2) sequence-based replication, wherein the gene region is sequenced in the replication sample and both known and novel variants are tested. The efficiency of the two strategies is dependent on the proportions of causative variants discovered in stage 1 and sequencing/genotyping errors. With rigorous population genetic and phenotypic models, it is demonstrated that sequence-based replication is consistently more powerful. However, the power gain is small (1) for large-scale studies with thousands of individuals, because a large fraction of causative variant sites can be observed and (2) for small- to medium-scale studies with a few hundred samples, because a large proportion of the locus population attributable risk can be explained by the uncovered variants. Therefore, genotyping can be a temporal solution for replicating genetic studies if stage 1 and 2 samples are drawn from the same population. However, sequence-based replication is advantageous if the stage 1 sample is small or novel variants discovery is also of interest. It is shown that currently attainable levels of sequencing error only minimally affect the comparison, and the advantage of sequence-based replication remains.\n"
],
"offsets": [
[
0,
1823
]
]
}
] | [] | [] | [] | [] |
193 | 20691405 | [
{
"id": "20691405__text",
"type": "abstract",
"text": [
"Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. Ectodermal dysplasias form a large disease family with more than 200 members. The combination of hair and tooth abnormalities, alopecia, and cutaneous syndactyly is characteristic of ectodermal dysplasia-syndactyly syndrome (EDSS). We used a homozygosity mapping approach to map the EDSS locus to 1q23 in a consanguineous Algerian family. By candidate gene analysis, we identified a homozygous mutation in the PVRL4 gene that not only evoked an amino acid change but also led to exon skipping. In an Italian family with two siblings affected by EDSS, we further detected a missense and a frameshift mutation. PVRL4 encodes for nectin-4, a cell adhesion molecule mainly implicated in the formation of cadherin-based adherens junctions. We demonstrated high nectin-4 expression in hair follicle structures, as well as in the separating digits of murine embryos, the tissues mainly affected by the EDSS phenotype. In patient keratinocytes, mutated nectin-4 lost its capability to bind nectin-1. Additionally, in discrete structures of the hair follicle, we found alterations of the membrane localization of nectin-afadin and cadherin-catenin complexes, which are essential for adherens junction formation, and we found reorganization of actin cytoskeleton. Together with cleft lip and/or palate ectodermal dysplasia (CLPED1, or Zlotogora-Ogur syndrome) due to an impaired function of nectin-1, EDSS is the second known \"nectinopathy\" caused by mutations in a nectin adhesion molecule.\n"
],
"offsets": [
[
0,
1592
]
]
}
] | [
{
"id": "20691405_T1",
"type": "Gene",
"text": [
"PVRL4"
],
"offsets": [
[
13,
18
]
],
"normalized": []
},
{
"id": "20691405_T3",
"type": "Gene",
"text": [
"PVRL4"
],
"offsets": [
[
520,
525
]
],
"normalized": []
},
{
"id": "20691405_T4",
"type": "Gene",
"text": [
"PVRL4"
],
"offsets": [
[
719,
724
]
],
"normalized": []
},
{
"id": "20691405_T2",
"type": "Gene",
"text": [
"nectin-4"
],
"offsets": [
[
52,
60
]
],
"normalized": []
},
{
"id": "20691405_T5",
"type": "Gene",
"text": [
"nectin-4"
],
"offsets": [
[
737,
745
]
],
"normalized": []
},
{
"id": "20691405_T6",
"type": "Gene",
"text": [
"nectin-4"
],
"offsets": [
[
1055,
1063
]
],
"normalized": []
},
{
"id": "20691405_T7",
"type": "Gene",
"text": [
"nectin-1"
],
"offsets": [
[
1092,
1100
]
],
"normalized": []
},
{
"id": "20691405_T8",
"type": "Gene",
"text": [
"nectin-1"
],
"offsets": [
[
1491,
1499
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20691405_R1",
"type": "Equals",
"arg1_id": "20691405_T2",
"arg2_id": "20691405_T1",
"normalized": []
},
{
"id": "20691405_R2",
"type": "Equals",
"arg1_id": "20691405_T5",
"arg2_id": "20691405_T4",
"normalized": []
}
] |
194 | 20920665 | [
{
"id": "20920665__text",
"type": "abstract",
"text": [
"Identification of copy number variation hotspots in human populations. Copy number variants (CNVs) in the human genome contribute to both Mendelian and complex traits as well as to genomic plasticity in evolution. The investigation of mutational rates of CNVs is critical to understanding genomic instability and the etiology of the copy number variation (CNV)-related traits. However, the evaluation of the CNV mutation rate at the genome level poses an insurmountable practical challenge that requires large samples and accurate typing. In this study, we show that an approximate estimation of the CNV mutation rate could be achieved by using the phylogeny information of flanking SNPs. This allows a genome-wide comparison of mutation rates between CNVs with the use of vast, readily available data of SNP genotyping. A total of 4187 CNV regions (CNVRs) previously identified in HapMap populations were investigated in this study. We showed that the mutation rates for the majority of these CNVRs are at the order of 10⁻⁵ per generation, consistent with experimental observations at individual loci. Notably, the mutation rates of 104 (2.5%) CNVRs were estimated at the order of 10⁻³ per generation; therefore, they were identified as potential hotspots. Additional analyses revealed that genome architecture at CNV loci has a potential role in inciting mutational hotspots in the human genome. Interestingly, 49 (47%) CNV hotspots include human genes, some of which are known to be functional CNV loci (e.g., CNVs of C4 and β-defensin causing autoimmune diseases and CNVs of HYDIN with implication in control of cerebral cortex size), implicating the important role of CNV in human health and evolution, especially in common and complex diseases.\n"
],
"offsets": [
[
0,
1751
]
]
}
] | [
{
"id": "20920665_T1",
"type": "Gene",
"text": [
"HYDIN"
],
"offsets": [
[
1579,
1584
]
],
"normalized": []
}
] | [] | [] | [] |
195 | 20226436 | [
{
"id": "20226436__text",
"type": "abstract",
"text": [
"A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1. To identify genetic susceptibility factors conferring increased risk of venous thrombosis (VT), we conducted a multistage study, following results of a previously published GWAS that failed to detect loci for developing VT. Using a collection of 5862 cases with VT and 7112 healthy controls, we identified the HIVEP1 locus on chromosome 6p24.1 as a susceptibility locus for VT. Indeed, the HIVEP1 rs169713C allele was associated with an increased risk for VT, with an odds ratio of 1.20 (95% confidence interval 1.13-1.27, p = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. The current results provide the identification of a locus involved in VT susceptibility that lies outside the traditional coagulation/fibrinolysis pathway.\n"
],
"offsets": [
[
0,
1011
]
]
}
] | [
{
"id": "20226436_T1",
"type": "Gene",
"text": [
"HIVEP1"
],
"offsets": [
[
440,
446
]
],
"normalized": []
},
{
"id": "20226436_T2",
"type": "Gene",
"text": [
"HIVEP1"
],
"offsets": [
[
520,
526
]
],
"normalized": []
},
{
"id": "20226436_T3",
"type": "Gene",
"text": [
"HIVEP1"
],
"offsets": [
[
673,
679
]
],
"normalized": []
}
] | [] | [] | [] |
196 | 20206336 | [
{
"id": "20206336__text",
"type": "abstract",
"text": [
"Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities. Segmental duplications, which comprise approximately 5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are approximately 2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is approximately 2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.\n"
],
"offsets": [
[
0,
1861
]
]
}
] | [
{
"id": "20206336_T1",
"type": "Gene",
"text": [
"TBX2"
],
"offsets": [
[
1611,
1615
]
],
"normalized": []
},
{
"id": "20206336_T2",
"type": "Gene",
"text": [
"TBX4"
],
"offsets": [
[
1620,
1624
]
],
"normalized": []
}
] | [] | [] | [] |
197 | 20537301 | [
{
"id": "20537301__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1043
]
]
}
] | [] | [] | [] | [] |
198 | 20970104 | [
{
"id": "20970104__text",
"type": "abstract",
"text": [
"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.\n"
],
"offsets": [
[
0,
1754
]
]
}
] | [
{
"id": "20970104_T1",
"type": "Gene",
"text": [
"NEXN"
],
"offsets": [
[
13,
17
]
],
"normalized": []
},
{
"id": "20970104_T2",
"type": "Gene",
"text": [
"NEXN"
],
"offsets": [
[
475,
479
]
],
"normalized": []
},
{
"id": "20970104_T3",
"type": "Gene",
"text": [
"NEXN"
],
"offsets": [
[
648,
652
]
],
"normalized": []
},
{
"id": "20970104_T4",
"type": "SNP",
"text": [
"c.391C>G"
],
"offsets": [
[
794,
802
]
],
"normalized": []
},
{
"id": "20970104_T5",
"type": "SNP",
"text": [
"p.Q131E"
],
"offsets": [
[
804,
811
]
],
"normalized": []
},
{
"id": "20970104_T6",
"type": "SNP",
"text": [
"c.835C>T"
],
"offsets": [
[
817,
825
]
],
"normalized": []
},
{
"id": "20970104_T7",
"type": "SNP",
"text": [
"p.R279C"
],
"offsets": [
[
827,
834
]
],
"normalized": []
},
{
"id": "20970104_T8",
"type": "Gene",
"text": [
"NEXN"
],
"offsets": [
[
873,
877
]
],
"normalized": []
},
{
"id": "20970104_T9",
"type": "SNP",
"text": [
"p.Q131E"
],
"offsets": [
[
1349,
1356
]
],
"normalized": []
},
{
"id": "20970104_T10",
"type": "SNP",
"text": [
"p.Q131E"
],
"offsets": [
[
1464,
1471
]
],
"normalized": []
},
{
"id": "20970104_T11",
"type": "Gene",
"text": [
"NEXN"
],
"offsets": [
[
1518,
1522
]
],
"normalized": []
},
{
"id": "20970104_T12",
"type": "Gene",
"text": [
"NEXN"
],
"offsets": [
[
1650,
1654
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20970104_R1",
"type": "AssociatedTo",
"arg1_id": "20970104_T7",
"arg2_id": "20970104_T8",
"normalized": []
},
{
"id": "20970104_R2",
"type": "AssociatedTo",
"arg1_id": "20970104_T6",
"arg2_id": "20970104_T8",
"normalized": []
},
{
"id": "20970104_R3",
"type": "AssociatedTo",
"arg1_id": "20970104_T5",
"arg2_id": "20970104_T8",
"normalized": []
},
{
"id": "20970104_R4",
"type": "AssociatedTo",
"arg1_id": "20970104_T4",
"arg2_id": "20970104_T8",
"normalized": []
}
] |
199 | 20021999 | [
{
"id": "20021999__text",
"type": "abstract",
"text": [
"Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2. We report a large Chinese family with X-linked postlingual nonsyndromic hearing impairment in which the critical linkage interval spans a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that overlaps the DFN2 locus. Mutation screening of the PRPS1 gene in this family and in the three previously reported DFN2 families identified four different missense mutations in PRPS1. These mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase 1 activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients. By in situ hybridization, we demonstrate expression of Prps1 in murine vestibular and cochlea hair cells, with continuous expression in hair cells and postnatal expression in the spiral ganglion. Being the second identified gene associated with X-linked nonsyndromic deafness, PRPS1 will be a good candidate gene for genetic testing for X-linked nonsyndromic hearing loss.\n"
],
"offsets": [
[
0,
1115
]
]
}
] | [
{
"id": "20021999_T1",
"type": "Gene",
"text": [
"PRPS1"
],
"offsets": [
[
34,
39
]
],
"normalized": []
},
{
"id": "20021999_T3",
"type": "Gene",
"text": [
"PRPS1"
],
"offsets": [
[
370,
375
]
],
"normalized": []
},
{
"id": "20021999_T2",
"type": "Gene",
"text": [
"PRPS1"
],
"offsets": [
[
495,
500
]
],
"normalized": []
},
{
"id": "20021999_T4",
"type": "Gene",
"text": [
"Prps1"
],
"offsets": [
[
797,
802
]
],
"normalized": []
},
{
"id": "20021999_T5",
"type": "Gene",
"text": [
"PRPS1"
],
"offsets": [
[
1019,
1024
]
],
"normalized": []
}
] | [] | [] | [] |