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22444671
[ "Mutations", "in", "the", "glycosylphosphatidylinositol", "gene", "PIGL", "glycosylphosphatidylinositol", " ", "gene", "PIGL", "cause", "CHIME", "syndrome.", "CHIME", "syndrome", "is", "characterized", "by", "colobomas,", "heart", "defects,", "ichthyosiform", "dermatosis,", "mental", "retardation", "(intellectual", "disability),", "and", "ear", "anomalies,", "including", "conductive", "hearing", "loss.", "Whole-exome", "sequencing", "on", "five", "previously", "reported", "cases", "identified", "PIGL", ",", "the", "de-N-acetylase", "required", "for", "glycosylphosphatidylinositol", "(GPI)", "anchor", "formation,", "as", "a", "strong", "candidate.", "Furthermore,", "cell", "lines", "derived", "from", "these", "cases", "had", "significantly", "reduced", "levels", "of", "the", "two", "GPI", "anchor", "markers,", "CD59", " ", "and", "a", "GPI-binding", "toxin,", "aerolysin", "(FLAER),", "confirming", "the", "pathogenicity", "of", "the", "mutations." ]
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Mutations in the glycosylphosphatidylinositol gene PIGL glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL , the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations.
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18252226
[ "Acetylcholine", "receptor", "pathway", "mutations", "explain", "various", "fetal", "akinesia", "deformation", "sequence", "disorders.", "Impaired", "fetal", "movement", "causes", "malformations,", "summarized", "as", "fetal", "akinesia", "deformation", "sequence", "(FADS),", "and", "is", "triggered", "by", "environmental", "and", "genetic", "factors.", "Acetylcholine", "receptor", " ", "(", "AChR", ")", "components", "are", "suspects", "because", "mutations", "in", "the", "fetally", "expressed", "gamma", "subunit", "(", "CHRNG", ")", "of", "AChR", " ", "were", "found", "in", "two", "FADS", "disorders,", "lethal", "multiple", "pterygium", "syndrome", "(LMPS)", "and", "Escobar", "syndrome.", "Other", "AChR", " ", "subunits", "alpha1,", "beta1,", "and", "delta", "(", "CHRNA1", ",", "CHRNB1", ",", "CHRND", ")", "as", "well", "as", "receptor-associated", "protein", "of", "the", "synapse", "(", "RAPSN", ")", "previously", "revealed", "missense", "or", "compound", "nonsense-missense", "mutations", "in", "viable", "congenital", "myasthenic", "syndrome;", "lethality", "of", "homozygous", "null", "mutations", "was", "predicted", "but", "never", "shown.", "We", "provide", "the", "first", "report", "to", "our", "knowledge", "of", "homozygous", "nonsense", "mutations", "in", "CHRNA1", " ", "and", "CHRND", " ", "and", "show", "that", "they", "were", "lethal,", "whereas", "novel", "recessive", "missense", "mutations", "in", "RAPSN", " ", "caused", "a", "severe", "but", "not", "necessarily", "lethal", "phenotype.", "To", "elucidate", "disease-associated", "malformations", "such", "as", "frequent", "abortions,", "fetal", "edema,", "cystic", "hygroma,", "or", "cardiac", "defects,", "we", "studied", "Chrna1", ",", "Chrnb1", ",", "Chrnd", ",", "Chrng", ",", "and", "Rapsn", " ", "in", "mouse", "embryos", "and", "found", "expression", "in", "skeletal", "muscles", "but", "also", "in", "early", "somite", "development.", "This", "indicates", "that", "early", "developmental", "defects", "might", "be", "due", "to", "somite", "expression", "in", "addition", "to", "solely", "muscle-specific", "effects.", "We", "conclude", "that", "complete", "or", "severe", "functional", "disruption", "of", "fetal", "AChR", " ", "causes", "lethal", "multiple", "pterygium", "syndrome", "whereas", "milder", "alterations", "result", "in", "fetal", "hypokinesia", "with", "inborn", "contractures", "or", "a", "myasthenic", "syndrome", "later", "in", "life." ]
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Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor ( AChR ) components are suspects because mutations in the fetally expressed gamma subunit ( CHRNG ) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta ( CHRNA1 , CHRNB1 , CHRND ) as well as receptor-associated protein of the synapse ( RAPSN ) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1 , Chrnb1 , Chrnd , Chrng , and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.
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8328456
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Anticipation in bipolar affective disorder. Anticipation refers to the increase in disease severity or decrease in age at onset in succeeding generations. This phenomenon, formerly ascribed to observation biases, correlates with the expansion of trinucleotide repeat sequences (TNRs) in some disorders. If present in bipolar affective disorder ( BPAD ), anticipation could provide clues to its genetic etiology. We compared age at onset and disease severity between two generations of 34 unilineal families ascertained for a genetic linkage study of BPAD . Life-table analyses showed a significant decrease in survival to first mania or depression from the first to the second generation (P < .001). Intergenerational pairwise comparisons showed both a significantly earlier age at onset (P < .001) and a significantly increased disease severity (P < .001) in the second generation. This difference was significant under each of four data-sampling schemes which excluded probands in the second generation. The second generation experienced onset 8.9-13.5 years earlier and illness 1.8-3.4 times more severe than did the first generation. In additional analyses, drug abuse, deaths of affected individuals prior to interview, decreased fertility, censoring of age at onset, and the cohort effect did not affect our results. We conclude that genetic anticipation occurs in this sample of unilineal BPAD families. These findings may implicate genes with expanding TNRs in the genetic etiology of BPAD .
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9718346
[ "A", "gene", "involved", "in", "XY", "sex", "reversal", "is", "located", "on", "chromosome", "9,", "distal", "to", "marker", "D9S1779.", "The", "genetic", "mechanisms", "involved", "in", "sex", "differentiation", "are", "poorly", "understood,", "and", "progress", "in", "identification", "of", "the", "genes", "involved", "has", "been", "slow.", "The", "fortuitous", "finding", "of", "chromosomal", "rearrangements", "in", "association", "with", "a", "sex-reversed", "phenotype", "has", "led", "to", "the", "isolation", "of", "SRY", " ", "and", "SOX9,", " ", "both", "shown", "to", "be", "involved", "in", "the", "sex-determining", "pathway.", "In", "addition,", "duplications", "of", "the", "X", "chromosome,", "deletions", "of", "chromosomes", "9", "and", "10,", "and", "translocations", "involving", "chromosome", "17", "have", "been", "reported", "to", "be", "associated", "with", "abnormal", "testicular", "differentiation,", "leading", "to", "male-to-female", "sex", "reversal", "in", "46,XY", "individuals.", "We", "present", "the", "cytogenetic", "and", "molecular", "analyses", "of", "four", "sex-reversed", "XY", "females,", "each", "with", "gonadal", "dysgenesis", "and", "other", "variable", "malformations,", "and", "with", "terminal", "deletions", "of", "distal", "chromosome", "9p,", "resulting", "from", "unbalanced", "autosomal", "translocations.", "PCR", "amplification", "and", "DNA", "sequence", "analysis", "of", "SRY", " ", "revealed", "no", "mutations", "in", "the", "high-mobility-group", "domain", "(i.e.,", "HMG", "box)", "in", "any", "of", "the", "four", "patients.", "Conventional", "and", "molecular", "cytogenetic", "analyses", "of", "metaphase", "chromosomes", "from", "each", "patient", "suggest", "that", "the", "smallest", "region", "of", "overlap", "(SRO)", "of", "deletions", "involves", "a", "very", "small", "region", "of", "distal", "band", "9p24.", "Loss-of-heterozygosity", "studies", "using", "17", "highly", "polymorphic", "microsatellite", "markers,", "as", "well", "as", "FISH", "using", "YAC", "clones", "corresponding", "to", "the", "most", "distal", "markers", "on", "9p,", "showed", "that", "the", "SRO", "lies", "distal", "to", "marker", "D9S1779.", "These", "results", "significantly", "narrow", "the", "putative", "sex-determining", "gene", "to", "the", "very", "terminal", "region", "of", "the", "short", "arm", "of", "chromosome", "9." ]
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A gene involved in XY sex reversal is located on chromosome 9, distal to marker D9S1779. The genetic mechanisms involved in sex differentiation are poorly understood, and progress in identification of the genes involved has been slow. The fortuitous finding of chromosomal rearrangements in association with a sex-reversed phenotype has led to the isolation of SRY and SOX9, both shown to be involved in the sex-determining pathway. In addition, duplications of the X chromosome, deletions of chromosomes 9 and 10, and translocations involving chromosome 17 have been reported to be associated with abnormal testicular differentiation, leading to male-to-female sex reversal in 46,XY individuals. We present the cytogenetic and molecular analyses of four sex-reversed XY females, each with gonadal dysgenesis and other variable malformations, and with terminal deletions of distal chromosome 9p, resulting from unbalanced autosomal translocations. PCR amplification and DNA sequence analysis of SRY revealed no mutations in the high-mobility-group domain (i.e., HMG box) in any of the four patients. Conventional and molecular cytogenetic analyses of metaphase chromosomes from each patient suggest that the smallest region of overlap (SRO) of deletions involves a very small region of distal band 9p24. Loss-of-heterozygosity studies using 17 highly polymorphic microsatellite markers, as well as FISH using YAC clones corresponding to the most distal markers on 9p, showed that the SRO lies distal to marker D9S1779. These results significantly narrow the putative sex-determining gene to the very terminal region of the short arm of chromosome 9.
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7977348
[ "Familial", "site-specific", "ovarian", "cancer", "is", "linked", "to", "BRCA1", " ", "on", "17q12-21.", "In", "a", "study", "of", "nine", "families", "with", "\"site-specific\"", "ovarian", "cancer", "(criterion:", "three", "or", "more", "cases", "of", "epithelial", "ovarian", "cancer", "and", "no", "cases", "of", "breast", "cancer", "diagnosed", "at", "age", "<", "50", "years)", "we", "have", "obtained", "evidence", "of", "linkage", "to", "the", "breast-ovarian", "cancer", "susceptibility", "gene,", "BRCA1", " ", "on", "17q12-21.", "If", "the", "risk", "of", "cancer", "in", "these", "families", "is", "assumed", "to", "be", "restricted", "to", "the", "ovary,", "the", "best", "estimate", "of", "the", "proportion", "of", "families", "linked", "to", "BRCA1", " ", "is", ".78", "(95%", "confidence", "interval", ".32-1.0).", "If", "predisposition", "to", "both", "breast", "and", "ovarian", "cancer", "is", "assumed,", "the", "proportion", "linked", "is", "1.0", "(95%", "confidence", "interval", ".46-1.0).", "The", "linkage", "of", "familial", "site-specific", "ovarian", "cancer", "to", "BRCA1", " ", "indicates", "the", "possibility", "of", "predictive", "testing", "in", "such", "families;", "however,", "this", "is", "only", "appropriate", "in", "families", "where", "the", "evidence", "for", "linkage", "to", "BRCA1", " ", "is", "conclusive." ]
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Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. In a study of nine families with "site-specific" ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age < 50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .32-1.0). If predisposition to both breast and ovarian cancer is assumed, the proportion linked is 1.0 (95% confidence interval .46-1.0). The linkage of familial site-specific ovarian cancer to BRCA1 indicates the possibility of predictive testing in such families; however, this is only appropriate in families where the evidence for linkage to BRCA1 is conclusive.
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9245996
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The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12. The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD.
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10762557
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Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.
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20598277
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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.
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1363805
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Mutations in the medium chain acyl-CoA dehydrogenase ( MCAD medium chain acyl-CoA dehydrogenase (MCAD) gene. Medium chain acyl-CoA dehydrogenase ( MCAD Medium chain acyl-CoA dehydrogenase (MCAD) catalyzes the first reaction of the beta-oxidation cycle for 4-10-carbon fatty acids. MCAD deficiency is one of the most frequent inborn metabolic disorders in populations of northwestern European origin. In the compilation of data from a worldwide study of 172 unrelated patients each representing an independent pedigree, a total of 8 different mutations have been identified. Among them, a single prevalent mutation, 985A-->G, was found in 90% of 344 variant alleles. 985A-->G causes glutamate substitution for lysine-304 in the mature MCAD subunit, which causes impairment of tetramer assembly and instability of the protein. Three of 7 rarer mutations have been identified in a few unrelated patients, while the remaining 4 have each been found in only a single pedigree. In addition to tabulating the mutations, the acyl-CoA dehydrogenase gene family, the structure of the MCAD gene and the evolution of 985A-->G MCAD acyl-CoA dehydrogenase 985A-->G , was found in 90% of 344 variant alleles. 985A-->G causes glutamate substitution for lysine-304 in the mature MCAD subunit, which causes impairment of tetramer assembly and instability of the protein. Three of 7 rarer mutations have been identified in a few unrelated patients, while the remaining 4 have each been found in only a single pedigree. In addition to tabulating the mutations, the acyl-CoA dehydrogenase gene family, the structure of the MCAD gene and the evolution of 985A-->G mutation are briefly discussed.
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18752264
[ "Ethnically", "diverse", "causes", "of", "Walker-Warburg", "syndrome", "(WWS):", "FCMD", "mutations", "are", "a", "more", "common", "cause", "of", "WWS", "outside", "of", "the", "Middle", "East.", "Walker-Warburg", "syndrome", "(WWS)", "is", "a", "genetically", "heterogeneous", "autosomal", "recessive", "disease", "characterized", "by", "congenital", "muscular", "dystrophy,", "cobblestone", "lissencephaly,", "and", "ocular", "malformations.", "Mutations", "in", "six", "genes", "involved", "in", "the", "glycosylation", "of", "á-dystroglycan", "(", "POMT1", ",", "POMT2", ",", "POMGNT1", ",", "FCMD", ",", "FKRP", " ", "and", "LARGE", ")", "have", "been", "identified", "in", "WWS", "patients,", "but", "account", "for", "only", "a", "portion", "of", "WWS", "cases.", "To", "better", "understand", "the", "genetics", "of", "WWS", "and", "establish", "the", "frequency", "and", "distribution", "of", "mutations", "across", "WWS", "genes,", "we", "genotyped", "all", "known", "loci", "in", "a", "cohort", "of", "43", "WWS", "patients", "of", "varying", "geographical", "and", "ethnic", "origin.", "Surprisingly,", "we", "reached", "a", "molecular", "diagnosis", "for", "40%", "of", "our", "patients", "and", "found", "mutations", "in", "POMT1", ",", "POMT2", ",", "FCMD", " ", "and", "FKRP", ",", "many", "of", "which", "were", "novel", "alleles,", "but", "no", "mutations", "in", "POMGNT1", " ", "or", "LARGE", ".", "Notably,", "the", "FCMD", " ", "gene", "was", "a", "more", "common", "cause", "of", "WWS", "than", "previously", "expected", "in", "the", "European/American", "subset", "of", "our", "cohort,", "including", "all", "Ashkenazi", "Jewish", "cases,", "who", "carried", "the", "same", "founder", "mutation." ]
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Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East. Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan ( POMT1 , POMT2 , POMGNT1 , FCMD , FKRP and LARGE ) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1 , POMT2 , FCMD and FKRP , many of which were novel alleles, but no mutations in POMGNT1 or LARGE . Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.
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9012405
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A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation ( T119P ) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH , and strongly support the concept of "transcription syndromes."
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17668385
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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.
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21882294
[ "SgD-CNV,", "a", "database", "for", "common", "and", "rare", "copy", "number", "variants", "in", "three", "Asian", "populations.", "Copy", "number", "variants", "(CNVs)", "extend", "our", "understanding", "of", "the", "genetic", "diversity", "in", "humans.", "However,", "the", "distribution", "and", "characteristics", "of", "CNVs", "in", "Asian", "populations", "remain", "largely", "unexplored,", "especially", "for", "rare", "CNVs", "that", "have", "emerged", "as", "important", "genetic", "factors", "for", "complex", "traits.", "In", "the", "present", "study,", "we", "performed", "an", "in-depth", "investigation", "of", "common", "and", "rare", "CNVs", "across", "8,148", "individuals", "from", "the", "three", "major", "Asian", "ethnic", "groups:", "Chinese", "(n", "=", "1,945),", "Malays", "(n", "=", "2,399),", "and", "Indians", "(n", "=", "2,217)", "in", "Singapore,", "making", "this", "investigation", "the", "most", "comprehensive", "genome-wide", "survey", "of", "CNVs", "outside", "the", "European-ancestry", "populations", "to", "date.", "We", "detected", "about", "16", "CNVs", "per", "individual", "and", "the", "ratio", "of", "loss", "to", "gain", "events", "is", "∼2:1.", "The", "majority", "of", "the", "CNVs", "are", "of", "low", "frequency", "(<10%),", "and", "40%", "are", "rare", "(<1%).", "In", "each", "population,", "∼20%", "of", "the", "CNVs", "are", "not", "previously", "catalogued", "in", "the", "Database", "of", "Genomic", "Variants", "(DGV).", "Contrary", "to", "findings", "from", "European", "studies,", "the", "common", "CNVs", "(>5%)", "in", "our", "populations", "are", "not", "well", "tagged", "by", "SNPs", "in", "Illumina", "1M", "and", "610K", "arrays,", "and", "most", "disease-associated", "common", "CNVs", "previously", "reported", "in", "Caucasians", "are", "rare", "in", "our", "populations.", "We", "also", "report", "noticeable", "population", "differentiation", "in", "the", "CNV", "landscape", "of", "these", "Asian", "populations,", "with", "the", "greatest", "diversity", "seen", "between", "the", "Indians", "and", "the", "Chinese." ]
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SgD-CNV, a database for common and rare copy number variants in three Asian populations. Copy number variants (CNVs) extend our understanding of the genetic diversity in humans. However, the distribution and characteristics of CNVs in Asian populations remain largely unexplored, especially for rare CNVs that have emerged as important genetic factors for complex traits. In the present study, we performed an in-depth investigation of common and rare CNVs across 8,148 individuals from the three major Asian ethnic groups: Chinese (n = 1,945), Malays (n = 2,399), and Indians (n = 2,217) in Singapore, making this investigation the most comprehensive genome-wide survey of CNVs outside the European-ancestry populations to date. We detected about 16 CNVs per individual and the ratio of loss to gain events is ∼2:1. The majority of the CNVs are of low frequency (<10%), and 40% are rare (<1%). In each population, ∼20% of the CNVs are not previously catalogued in the Database of Genomic Variants (DGV). Contrary to findings from European studies, the common CNVs (>5%) in our populations are not well tagged by SNPs in Illumina 1M and 610K arrays, and most disease-associated common CNVs previously reported in Caucasians are rare in our populations. We also report noticeable population differentiation in the CNV landscape of these Asian populations, with the greatest diversity seen between the Indians and the Chinese.
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15386213
[ "Statistical", "tests", "for", "admixture", "mapping", "with", "case-control", "and", "cases-only", "data.", "Admixture", "mapping", "is", "a", "promising", "new", "tool", "for", "discovering", "genes", "that", "contribute", "to", "complex", "traits.", "This", "mapping", "approach", "uses", "samples", "from", "recently", "admixed", "populations", "to", "detect", "susceptibility", "loci", "at", "which", "the", "risk", "alleles", "have", "different", "frequencies", "in", "the", "original", "contributing", "populations.", "Although", "the", "idea", "for", "admixture", "mapping", "has", "been", "around", "for", "more", "than", "a", "decade,", "the", "genomic", "tools", "are", "only", "now", "becoming", "available", "to", "make", "this", "a", "feasible", "and", "attractive", "option", "for", "complex-trait", "mapping.", "In", "this", "article,", "we", "describe", "new", "statistical", "methods", "for", "analyzing", "multipoint", "data", "from", "admixture-mapping", "studies", "to", "detect", "\"ancestry", "association.\"", "The", "new", "test", "statistics", "do", "not", "assume", "a", "particular", "disease", "model;", "instead,", "they", "are", "based", "simply", "on", "the", "extent", "to", "which", "the", "sample's", "ancestry", "proportions", "at", "a", "locus", "deviate", "from", "the", "genome", "average.", "Our", "power", "calculations", "show", "that,", "for", "loci", "at", "which", "the", "underlying", "risk-allele", "frequencies", "are", "substantially", "different", "in", "the", "ancestral", "populations,", "the", "power", "of", "admixture", "mapping", "can", "be", "comparable", "to", "that", "of", "association", "mapping", "but", "with", "a", "far", "smaller", "number", "of", "markers.", "We", "also", "show", "that,", "although", "\"ancestry", "informative", "markers\"", "(AIMs)", "are", "superior", "to", "random", "single-nucleotide", "polymorphisms", "(SNPs),", "random", "SNPs", "can", "perform", "quite", "well", "when", "AIMs", "are", "not", "available.", "Hence,", "researchers", "who", "study", "admixed", "populations", "in", "which", "AIMs", "are", "not", "available", "can", "perform", "admixture", "mapping", "with", "the", "use", "of", "modestly", "higher", "densities", "of", "random", "markers.", "Software", "to", "perform", "the", "gene-mapping", "calculations,", "\"MALDsoft,\"", "is", "freely", "available", "on", "the", "Pritchard", "Lab", "Web", "site." ]
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Statistical tests for admixture mapping with case-control and cases-only data. Admixture mapping is a promising new tool for discovering genes that contribute to complex traits. This mapping approach uses samples from recently admixed populations to detect susceptibility loci at which the risk alleles have different frequencies in the original contributing populations. Although the idea for admixture mapping has been around for more than a decade, the genomic tools are only now becoming available to make this a feasible and attractive option for complex-trait mapping. In this article, we describe new statistical methods for analyzing multipoint data from admixture-mapping studies to detect "ancestry association." The new test statistics do not assume a particular disease model; instead, they are based simply on the extent to which the sample's ancestry proportions at a locus deviate from the genome average. Our power calculations show that, for loci at which the underlying risk-allele frequencies are substantially different in the ancestral populations, the power of admixture mapping can be comparable to that of association mapping but with a far smaller number of markers. We also show that, although "ancestry informative markers" (AIMs) are superior to random single-nucleotide polymorphisms (SNPs), random SNPs can perform quite well when AIMs are not available. Hence, researchers who study admixed populations in which AIMs are not available can perform admixture mapping with the use of modestly higher densities of random markers. Software to perform the gene-mapping calculations, "MALDsoft," is freely available on the Pritchard Lab Web site.
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10677322
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Estimation of variance components of quantitative traits in inbred populations. Use of variance-component estimation for mapping of quantitative-trait loci in humans is a subject of great current interest. When only trait values, not genotypic information, are considered, variance-component estimation can also be used to estimate heritability of a quantitative trait. Inbred pedigrees present special challenges for variance-component estimation. First, there are more variance components to be estimated in the inbred case, even for a relatively simple model including additive, dominance, and environmental effects. Second, more identity coefficients need to be calculated from an inbred pedigree in order to perform the estimation, and these are computationally more difficult to obtain in the inbred than in the outbred case. As a result, inbreeding effects have generally been ignored in practice. We describe here the calculation of identity coefficients and estimation of variance components of quantitative traits in large inbred pedigrees, using the example of HDL in the Hutterites. We use a multivariate normal model for the genetic effects, extending the central-limit theorem of Lange to allow for both inbreeding and dominance under the assumptions of our variance-component model. We use simulated examples to give an indication of under what conditions one has the power to detect the additional variance components and to examine their impact on variance-component estimation. We discuss the implications for mapping and heritability estimation by use of variance components in inbred populations.
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16909392
[ "Navajo", "neurohepatopathy", "is", "caused", "by", "a", "mutation", "in", "the", "MPV17", " ", "gene.", "Navajo", "neurohepatopathy", "(NNH)", "is", "an", "autosomal", "recessive", "disease", "that", "is", "prevalent", "among", "Navajo", "children", "in", "the", "southwestern", "United", "States.", "The", "major", "clinical", "features", "are", "hepatopathy,", "peripheral", "neuropathy,", "corneal", "anesthesia", "and", "scarring,", "acral", "mutilation,", "cerebral", "leukoencephalopathy,", "failure", "to", "thrive,", "and", "recurrent", "metabolic", "acidosis", "with", "intercurrent", "infections.", "Infantile,", "childhood,", "and", "classic", "forms", "of", "NNH", "have", "been", "described.", "Mitochondrial", "DNA", "(mtDNA)", "depletion", "was", "detected", "in", "the", "livers", "of", "two", "patients,", "suggesting", "a", "primary", "defect", "in", "mtDNA", "maintenance.", "Homozygosity", "mapping", "of", "two", "families", "with", "NNH", "suggested", "linkage", "to", "chromosome", "2p24.", "This", "locus", "includes", "the", "MPV17", " ", "gene,", "which,", "when", "mutated,", "causes", "a", "hepatocerebral", "form", "of", "mtDNA", "depletion.", "Sequencing", "of", "the", "MPV17", "gene", "in", "six", "patients", "with", "NNH", "from", "five", "families", "revealed", "the", "homozygous", "R50Q", "MPV17", " ", "gene", "in", "six", "patients", "with", "NNH", "from", "five", "families", "revealed", "the", "homozygous", "R50Q", "mutation", "described", "elsewhere.", "Identification", "of", "a", "single", "missense", "mutation", "in", "patients", "with", "NNH", "confirms", "that", "the", "disease", "is", "probably", "due", "to", "a", "founder", "effect", "and", "extends", "the", "phenotypic", "spectrum", "associated", "with", "MPV17", " ", "mutations." ]
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Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.
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8257990
[ "Base", "substitutions", "in", "the", "human", "dystrophin", "gene:", "detection", "by", "using", "the", "single-strand", "conformation", "polymorphism", "(SSCP)", "technique.", "We", "have", "established", "the", "experimental", "conditions", "to", "screen", "twenty", "regions", "of", "the", "dystrophin", "gene", "using", "the", "method", "of", "single-strand", "conformational", "polymorphism", "(SSCP)", "analysis.", "The", "aim", "of", "this", "study", "was", "to", "identify", "point", "mutations", "in", "patients", "with", "Duchenne", "or", "Becker", "muscular", "dystrophy", "(DMD", "or", "BMD)", "who", "have", "no", "gross", "DNA", "rearrangements", "detectable", "by", "Southern", "blot", "analysis", "or", "multiplex", "exon", "amplification.", "The", "investigation", "of", "thirteen", "patients", "using", "this", "procedure", "resulted", "in", "the", "detection", "of", "seven", "sequence", "polymorphisms", "(four", "identified", "in", "this", "study)", "that", "will", "be", "useful", "allelic", "markers", "in", "familial", "DNA", "analysis.", "Three", "rare", "sequence", "variants", "could", "be", "found", "(two", "of", "them", "being", "novel", "variants)", "but", "we", "were", "unable", "to", "demonstrate", "mutations", "that", "could", "be", "clearly", "sufficient", "to", "be", "responsible", "for", "the", "phenotype.", "This", "analysis", "confirmed", "the", "efficiency", "of", "the", "SSCP", "technique", "for", "the", "detection", "of", "nucleotide", "substitutions.", "Application", "of", "this", "approach", "to", "mutation", "or", "polymorphism", "detection", "to", "other", "exons", "of", "the", "gene", "will", "improve", "carrier", "and", "prenatal", "diagnosis." ]
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Base substitutions in the human dystrophin gene: detection by using the single-strand conformation polymorphism (SSCP) technique. We have established the experimental conditions to screen twenty regions of the dystrophin gene using the method of single-strand conformational polymorphism (SSCP) analysis. The aim of this study was to identify point mutations in patients with Duchenne or Becker muscular dystrophy (DMD or BMD) who have no gross DNA rearrangements detectable by Southern blot analysis or multiplex exon amplification. The investigation of thirteen patients using this procedure resulted in the detection of seven sequence polymorphisms (four identified in this study) that will be useful allelic markers in familial DNA analysis. Three rare sequence variants could be found (two of them being novel variants) but we were unable to demonstrate mutations that could be clearly sufficient to be responsible for the phenotype. This analysis confirmed the efficiency of the SSCP technique for the detection of nucleotide substitutions. Application of this approach to mutation or polymorphism detection to other exons of the gene will improve carrier and prenatal diagnosis.
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7717407
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Human T-cell receptor V beta gene polymorphism and multiple sclerosis. Population-based genetic associations have been reported between RFLPs detected with probes corresponding to the genes encoding the beta chain of the T-cell receptor for antigen (TCRB) and a variety of autoimmune disorders. In the case of multiple sclerosis (MS), these studies have localized a putative disease-associated gene to a region of approximately 110 kb in length, located within the TCRB Human T-cell receptor V beta gene polymorphism and multiple sclerosis. Population-based genetic associations have been reported between RFLPs detected with probes corresponding to the genes encoding the beta chain of the T-cell receptor for antigen (TCRB) and a variety of autoimmune disorders. In the case of multiple sclerosis (MS), these studies have localized a putative disease-associated gene to a region of approximately 110 kb in length, located within the TCRB locus. In the current study, all 14 known TCRBV (variable region) genes within the region of localization were mapped and identified. The nucleotide sequences of these genes were determined in a panel of six MS patients and six healthy controls, who were human-leukocyte antigen and TCRB-RFLP haplotype matched. Nine of the 14 TCRBV genes studied showed evidence of polymorphism. PCR-based assays for each of these polymorphic genes were developed, and allele and genotype frequencies were determined in a panel of DNA samples from 48 MS patients and 60 control individuals. No significant differences in allele, genotype, or phenotype frequencies were observed between the MS patients and controls for any of the 14 TCRBV-gene polymorphisms studied. In light of the extensive linkage disequilibrium across the region studied, the saturating numbers of polymorphisms examined, and the direct sequence analysis of all BV genes in the region, these results suggest that it is unlikely that germ-line polymorphism in the TCRBV locus makes a major contribution to MS susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)
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15372378
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A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B ( VAPB vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.
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12424708
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Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H . Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L , V1197A , or R1210C factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H factor H mutations associated with atypical hemolytic uremic syndrome. Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies.
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Likelihood methods for locating disease genes in nonequilibrium populations. Until recently, attempts to map disease genes on the basis of population associations with linked markers have been based on expected values of linkage disequilibrium. These methods suffer from the large variances imposed on disequilibrium measures by the evolutionary process, but a more serious problem for many diseases is that they assume an equilibrium population. For diseases that arose only a few hundred generations ago, it is more appropriate to concentrate on the initial growth phase of the disease. We invoke a Poisson branching process for this early growth, and estimate the likelihood for the recombination fraction between marker and disease loci, on the basis of simulated disease populations. The limits of the resulting support intervals for the recombination fraction vary inversely with the age of the disease in generations. We illustrate the procedure with data on cystic fibrosis and diastrophic dysplasia, for which the method appears appropriate, and for Friedreich ataxia and Huntington disease, for which it does not. A valuable aspect of the method is the ability in some cases to compare likelihoods of the three orders for a disease locus and two linked marker loci.
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16358216
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A novel framework for sib pair linkage analysis. Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide array of choices for the analyst. To begin, we systematically classify the major sources of discretion in sib pair linkage analysis. Then, we extend the work of Kruglyak and Lander (1995), to bring the various forms into a unified framework and to facilitate a more general approach to the analysis. Finally, we describe a new, freely available computer program, Splat (Sib Pair Linkage Analysis Testing), that can perform any sib pair statistical test currently in use, as well as any user-defined test yet to be proposed. Splat uses the expectation maximization algorithm to calculate maximum-likelihood estimates of sharing (subject to user-specified conditions) and then plots LOD scores versus chromosomal position. It includes a novel grid-scanning capability that enables simultaneous visualization of multiple test statistics. This can lead to further insight into the genetic basis of the disease process under consideration. In addition, phenotype definitions can be modified without the recalculation of inheritance vectors, thereby providing considerable flexibility for exploratory analysis. The application of Splat will be illustrated with data from studies on the genetics of diabetic nephropathy.
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15459972
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Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early-onset osteoarthritis. Six genes responsible for MED have been identified, including COMP , COL9A1 , COL9A2 , COL9A3 , DSTDT and MATN3 . MATN3 encodes matrilin-3 , a cartilage-specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the beta-sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation ( p.F105S ) is located outside the beta-sheet region, within an alpha-helix region.
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1415265
[ "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." ]
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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.
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11102997
[ "A", "de", "novo", "adrenoleukodystrophy", "gene", "(", "ABCD1", "adrenoleukodystrophy", " ", "gene", "(ABCD1)", "mutation", "S636I", " ", "without", "detectable", "ABCD1", " ", "protein", "and", "a", "R104C", " ", "mutation", "with", "normal", "amounts", "of", "protein", "from", "an", "Austrian", "patient", "collective." ]
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A de novo adrenoleukodystrophy gene ( ABCD1 adrenoleukodystrophy gene (ABCD1) mutation S636I without detectable ABCD1 protein and a R104C mutation with normal amounts of protein from an Austrian patient collective.
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9838272
[ "The", "sib", "transmission/disequilibrium", "test", "is", "a", "Mantel-Haenszel", "test." ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
The sib transmission/disequilibrium test is a Mantel-Haenszel test.
[ 2, 1920, 9643, 5303, 19, 19264, 2648, 1977, 43, 26425, 17, 2118, 2099, 22996, 2648, 18, 3 ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]
[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
7866409
[ "Mutation", "at", "the", "catalytic", "site", "(", "M519V", ")", "in", "glycogen", "storage", "disease", "type", "II", "(Pompe", "disease)." ]
[ 0, 0, 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Mutation at the catalytic site ( M519V ) in glycogen storage disease type II (Pompe disease).
[ 2, 3979, 2019, 1920, 6804, 3200, 12, 24862, 4136, 1020, 13, 1922, 13302, 7451, 2573, 2601, 2890, 12, 12586, 9626, 2573, 13, 18, 3 ]
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[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]
[ -100, 0, 0, 0, 0, 0, 0, 3, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
12673802
[ "Oculopharyngeal", "muscular", "dystrophy", "(OPMD)", "due", "to", "a", "small", "duplication", "in", "the", "PABPN1", " ", "gene.", "Oculopharyngeal", "muscular", "dystrophy", "(OPMD)", "is", "a", "late", "onset", "autosomal", "dominant", "muscle", "disorder.", "The", "OPMD-locus", "has", "been", "mapped", "to", "chromosome", "14q11.2-q13.", "The", "polyadenylate", "binding", "protein", "nuclear", "1", "(PABPN1;", "PABP2", "PABPN1", "polyadenylate", "binding", "protein", "nuclear", "1", " ", "(PABPN1;", "PABP2)", "gene", "has", "been", "identified", "as", "the", "mutated", "gene.", "The", "mutation", "consists", "of", "a", "short", "meiotically", "stable", "trinucleotide", "repeat", "in", "the", "first", "exon", "of", "PABPN1", " ", "gene.", "We", "have", "investigated", "Dutch", "OPMD", "patients", "from", "four", "unrelated", "families", "and", "identified", "a", "new", "mutation", "in", "two", "of", "the", "four", "families.", "Instead", "of", "a", "repeat", "expansion", "we", "found", "a", "duplication", "in", "the", "first", "exon", "of", "the", "PABPN1", " ", "gene", "(", "c.27_28ins12", ",", "p.11_12insAAAA", ").", "The", "identification", "of", "this", "new", "mutation", "supports", "the", "theory", "of", "unequal", "crossing-over", "as", "molecular", "mechanism", "causing", "the", "mutation", "in", "the", "PABPN1", " ", "gene", "responsible", "for", "OPMD,", "and", "not", "the", "slippage", "model." ]
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Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene. Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. The OPMD-locus has been mapped to chromosome 14q11.2-q13. The polyadenylate binding protein nuclear 1 (PABPN1; PABP2 PABPN1 polyadenylate binding protein nuclear 1 (PABPN1; PABP2) gene has been identified as the mutated gene. The mutation consists of a short meiotically stable trinucleotide repeat in the first exon of PABPN1 gene. We have investigated Dutch OPMD patients from four unrelated families and identified a new mutation in two of the four families. Instead of a repeat expansion we found a duplication in the first exon of the PABPN1 gene ( c.27_28ins12 , p.11_12insAAAA ). The identification of this new mutation supports the theory of unequal crossing-over as molecular mechanism causing the mutation in the PABPN1 gene responsible for OPMD, and not the slippage model.
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20506298
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Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel. The CNGA3 gene encodes the A3 subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, an essential component of the phototransduction cascade. Certain mutations in CNGA3 cause autosomal recessive achromatopsia, a retinal disorder characterized by severely reduced visual acuity, lack of color discrimination, photophobia, and nystagmus. We identified three novel mutations in the pore-forming region of CNGA3 ( L363P , G367V , and E376K ) in patients diagnosed with achromatopsia. We assessed the expression and function of channels with these three new and two previously described mutations ( S341P and P372S ) in a heterologous HEK293 cell expression system using Western blot, subcellular localization on the basis of immunocytochemistry, calcium imaging, and patch clamp recordings. In this first comparative functional analysis of disease-associated mutations in the pore of a CNG channel, we found impaired surface expression of S341P , L363P , and P372S mutants and reduced macroscopic currents for channels with the mutations S341P , G367V , and E376K . Calcium imaging and patch clamp experiments after incubation at 37 degrees C revealed nonfunctional homo- and heteromeric channels in all five mutants, but incubation at 27 degrees C combined with coexpression of the B3 subunit restored residual function of channels with the mutations S341P , G367V , and E376K .
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15759212
[ "Identifying", "candidate", "Hirschsprung", "disease-associated", "RET", "variants.", "Patients", "with", "sporadic", "Hirschsprung", "disease", "(HSCR)", "show", "increased", "allele", "sharing", "at", "markers", "in", "the", "5'", "region", "of", "the", "RET", " ", "locus,", "indicating", "the", "presence", "of", "a", "common", "ancestral", "RET", " ", "mutation.", "In", "a", "previous", "study,", "we", "found", "a", "haplotype", "of", "six", "SNPs", "that", "was", "transmitted", "to", "55.6%", "of", "our", "patients,", "whereas", "it", "was", "present", "in", "only", "16.2%", "of", "the", "controls", "we", "used.", "Among", "the", "patients", "with", "that", "haplotype,", "90.8%", "had", "it", "on", "both", "chromosomes,", "which", "led", "to", "a", "much", "higher", "risk", "of", "developing", "HSCR", "than", "when", "the", "haplotype", "occurred", "heterozygously.", "To", "more", "precisely", "define", "the", "HSCR-associated", "region", "and", "to", "identify", "candidate", "disease-associated", "variant(s),", "we", "sequenced", "the", "shared", "common", "haplotype", "region", "from", "10", "kb", "upstream", "of", "the", "RET", "RET", " ", "variants.", "Patients", "with", "sporadic", "Hirschsprung", "disease", "(HSCR)", "show", "increased", "allele", "sharing", "at", "markers", "in", "the", "5'", "region", "of", "the", "RET", "locus,", "indicating", "the", "presence", "of", "a", "common", "ancestral", "RET", "mutation.", "In", "a", "previous", "study,", "we", "found", "a", "haplotype", "of", "six", "SNPs", "that", "was", "transmitted", "to", "55.6%", "of", "our", "patients,", "whereas", "it", "was", "present", "in", "only", "16.2%", "of", "the", "controls", "we", "used.", "Among", "the", "patients", "with", "that", "haplotype,", "90.8%", "had", "it", "on", "both", "chromosomes,", "which", "led", "to", "a", "much", "higher", "risk", "of", "developing", "HSCR", "than", "when", "the", "haplotype", "occurred", "heterozygously.", "To", "more", "precisely", "define", "the", "HSCR-associated", "region", "and", "to", "identify", "candidate", "disease-associated", "variant(s),", "we", "sequenced", "the", "shared", "common", "haplotype", "region", "from", "10", "kb", "upstream", "of", "the", "RET", "gene", "through", "intron", "1", "and", "exon", "2", "(in", "total,", "33", "kb)", "in", "a", "patient", "homozygous", "for", "the", "common", "risk", "haplotype", "and", "in", "a", "control", "individual", "homozygous", "for", "the", "most", "common", "nonrisk", "haplotype.", "A", "comparison", "of", "these", "sequences", "revealed", "86", "sequence", "differences.", "Of", "these", "86", "variations,", "8", "proved", "to", "be", "in", "regions", "highly", "conserved", "among", "different", "vertebrates", "and", "within", "putative", "transcription", "factor", "binding", "sites.", "We", "therefore", "considered", "these", "as", "candidate", "disease-associated", "variants.", "Subsequent", "genotyping", "of", "these", "eight", "variants", "revealed", "a", "strong", "disease", "association", "for", "six", "of", "the", "eight", "markers.", "These", "six", "markers", "also", "showed", "the", "largest", "distortions", "in", "allele", "transmission.", "Interspecies", "comparison", "showed", "that", "only", "one", "of", "the", "six", "variations", "was", "located", "in", "a", "region", "also", "conserved", "in", "a", "nonmammalian", "species,", "making", "it", "the", "most", "likely", "candidate", "HSCR-associated", "variant." ]
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Identifying candidate Hirschsprung disease-associated RET variants. Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET RET variants. Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant.
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19576569
[ "Diverse", "evolutionary", "histories", "for", "beta-adrenoreceptor", "genes", "in", "humans.", "In", "humans,", "three", "genes--", "ADRB1", ",", "ADRB2", " ", "and", "ADRB3", "--encode", "beta-adrenoreceptors", "(ADRB);", "these", "molecules", "mediate", "the", "action", "of", "catecholamines", "in", "multiple", "tissues", "and", "play", "pivotal", "roles", "in", "cardiovascular,", "respiratory,", "metabolic,", "and", "immunological", "functions.", "Genetic", "variants", "in", "ADRB", "genes", "have", "been", "associated", "with", "widespread", "diseases", "and", "conditions,", "but", "inconsistent", "results", "have", "often", "been", "obtained.", "Here,", "we", "addressed", "the", "recent", "evolutionary", "history", "of", "ADRB", "genes", "in", "human", "populations.", "Although", "ADRB1", " ", "is", "neutrally", "evolving,", "most", "tests", "rejected", "neutral", "evolution", "for", "ADRB2", " ", "in", "European,", "African,", "and", "Asian", "population", "samples.", "Analysis", "of", "inferred", "haplotypes", "for", "ADRB2", " ", "revealed", "three", "major", "clades", "with", "a", "coalescence", "time", "of", "1-1.5", "million", "years,", "suggesting", "that", "the", "gene", "is", "either", "subjected", "to", "balancing", "selection", "or", "undergoing", "a", "selective", "sweep.", "Haplotype", "analysis", "also", "revealed", "ethnicity-specific", "differences.", "Additionally,", "we", "observed", "significant", "deviations", "from", "Hardy-Weinberg", "equilibrium", "(HWE)", "for", "ADRB2", " ", "genotypes", "in", "distinct", "European", "cohorts;", "HWE", "deviation", "depends", "on", "sex", "(only", "females", "are", "in", "disequilibrium),", "and", "genotypes", "displaying", "maximum", "and", "minimum", "relative", "fitness", "differ", "across", "population", "samples,", "suggesting", "a", "complex", "situation", "possibly", "involving", "epistasis", "or", "maternal", "selection.", "Overall,", "our", "data", "indicate", "that", "future", "association", "studies", "involving", "ADRB2", " ", "will", "benefit", "from", "taking", "into", "account", "ethnicity-specific", "haplotype", "distributions", "and", "sex-based", "effects.", "With", "respect", "to", "ADRB3", ",", "our", "data", "indicate", "that", "the", "gene", "has", "been", "subjected", "to", "a", "selective", "sweep", "in", "African", "populations,", "the", "Trp64", "variant", "possibly", "representing", "the", "selection", "target.", "Given", "the", "previous", "association", "of", "the", "ancestral", "ADRB3", " ", "Arg64", "allele", "with", "obesity", "and", "type", "2", "diabetes,", "dietary", "adaptations", "might", "represent", "the", "underlying", "selective", "force." ]
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Diverse evolutionary histories for beta-adrenoreceptor genes in humans. In humans, three genes-- ADRB1 , ADRB2 and ADRB3 --encode beta-adrenoreceptors (ADRB); these molecules mediate the action of catecholamines in multiple tissues and play pivotal roles in cardiovascular, respiratory, metabolic, and immunological functions. Genetic variants in ADRB genes have been associated with widespread diseases and conditions, but inconsistent results have often been obtained. Here, we addressed the recent evolutionary history of ADRB genes in human populations. Although ADRB1 is neutrally evolving, most tests rejected neutral evolution for ADRB2 in European, African, and Asian population samples. Analysis of inferred haplotypes for ADRB2 revealed three major clades with a coalescence time of 1-1.5 million years, suggesting that the gene is either subjected to balancing selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. Additionally, we observed significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depends on sex (only females are in disequilibrium), and genotypes displaying maximum and minimum relative fitness differ across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Overall, our data indicate that future association studies involving ADRB2 will benefit from taking into account ethnicity-specific haplotype distributions and sex-based effects. With respect to ADRB3 , our data indicate that the gene has been subjected to a selective sweep in African populations, the Trp64 variant possibly representing the selection target. Given the previous association of the ancestral ADRB3 Arg64 allele with obesity and type 2 diabetes, dietary adaptations might represent the underlying selective force.
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12442283
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Novel mutations in the MYOC /GLC1A gene in a large group of glaucoma patients. Mutations at the myocilin ( MYOC myocilin (MYOC) gene within the GLC1A locus have been revealed in 2-4% of patients suffering primary open angle glaucoma (POAG) worldwide. In our ongoing glaucoma study six hundred eighty two persons have been screened for MYOC mutations. The first group consisted of 453 patients from a long-term clinical study diagnosed either with juvenile OAG (JOAG), POAG, ocular hypertension (OHT) or normal tension glaucoma (NTG) plus 22 cases of secondary glaucoma. This group, and additional 83 healthy controls, is part of a long term study with repeated clinical examinations at the University of Erlangen-Nurnberg. An additional sample of 124 glaucoma patients or at risk persons referred from other sources were included in the mutation screening. Five novel mutations, namely Gly434Ser , Asn450Asp , Val251Ala , Ile345Met and Ser393Asn , could be identified as cause of preperimetric POAG, JOAG, normal tension POAG and POAG. Myocilin mutations were identified similar with previous reports with other ethnic populations at the rate of 11/341 (3.2%) probands.
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9399915
[ "Centromere", "DNA", "dynamics:", "latent", "centromeres", "and", "neocentromere", "formation." ]
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Centromere DNA dynamics: latent centromeres and neocentromere formation.
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8503442
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The haplotype-relative-risk (HRR) method for analysis of association in nuclear families. One major problem in studying an association between a marker locus and a disease is the selection of an appropriate group of controls. However, this problem of population stratification can be circumvented in a quite elegant manner by family-based methods. The haplotype-relative-risk (HRR) method, which samples nuclear families with a single affected child and uses the parental haplotypes not transmitted to that child as a control individual, represents such a method for estimating the relative risk of a marker phenotype. In the special case of a recessive disease, it was already known that the equivalence of the HRR method with the classical relative risk (RR) obtained from independent samples holds only if the probability theta of a recombination between marker and disease locus is zero. We extend this result to an arbitrary mode of inheritance. Furthermore, we compare the distribution of the estimators for HRR and RR and show that, in the case of a positive linkage disequilibrium between a marker and disease allele, the distribution of the estimator for HRR is (stochastically) smaller than that for RR, irrespective of the recombination fraction. The practical implication of this result is that, for the HRR method, there is no tendency to give unduly high risk estimators, even for theta > 0. Finally, we give an expression for the standard error of the estimator for HRR by taking into account the nonindependence of transmitted and nontransmitted parental marker alleles in the case of theta > 0.
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17503332
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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.
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9718347
[ "Molecular", "analysis", "of", "9p", "deletions", "associated", "with", "XY", "sex", "reversal:", "refining", "the", "localization", "of", "a", "sex-determining", "gene", "to", "the", "tip", "of", "the", "chromosome." ]
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Molecular analysis of 9p deletions associated with XY sex reversal: refining the localization of a sex-determining gene to the tip of the chromosome.
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7981715
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Complex arylsulfatase A alleles causing metachromatic leukodystrophy. Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile metachromatic leukodystrophy revealed that the patient is a compound heterozygote of two alleles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation ( Gly122 > Ser ). The splice donor site mutation and the Gly122 > Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly154 > Asp and a Pro167 > Arg substitution. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into baby hamster kidney cells expression of arylsulfatase A activity could not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients' fibroblasts show that the enzyme carrying both mutations is synthesized in almost normal amounts but is rapidly degraded in an early biosynthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in metachromatic leukodystrophy and as far as lysosomal storage diseases are concerned have so far only been described in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease.
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18726931
[ "FOXL2", " ", "mutations", "and", "genomic", "rearrangements", "in", "BPES.", "The", "FOXL2", " ", "gene", "is", "one", "of", "10", "forkhead", "genes,", "the", "mutations", "of", "which", "lead", "to", "human", "developmental", "disorders,", "often", "with", "ocular", "manifestations.", "Mutations", "in", "FOXL2", "are", "known", "to", "cause", "blepharophimosis", "syndrome", "(BPES),", "an", "autosomal", "dominant", "eyelid", "malformation", "associated", "(type", "I)", "or", "not", "(type", "II)", "with", "ovarian", "dysfunction,", "leading", "to", "premature", "ovarian", "failure", "(POF).", "In", "addition,", "a", "few", "mutations", "have", "been", "described", "in", "patients", "with", "isolated", "POF.", "Here,", "we", "review", "all", "currently", "described", "FOXL2", " ", "sequence", "variations", "and", "genomic", "rearrangements", "in", "BPES", "and", "POF.", "Using", "a", "combined", "mutation", "detection", "approach,", "it", "is", "possible", "to", "identify", "the", "underlying", "genetic", "defect", "in", "a", "major", "proportion", "(88%)", "of", "typical", "BPES", "patients.", "Of", "all", "genetic", "defects", "found", "in", "our", "BPES", "cohort,", "intragenic", "mutations", "represent", "81%.", "They", "include", "missense", "changes,", "frameshift", "and", "nonsense", "mutations,", "in-frame", "deletions,", "and", "duplications,", "that", "are", "distributed", "along", "the", "single-exon", "gene.", "Genomic", "rearrangements", "comprising", "both", "deletions", "encompassing", "FOXL2", " ", "and", "deletions", "located", "outside", "its", "transcription", "unit,", "represent", "12%", "and", "5%", "of", "all", "genetic", "defects", "in", "our", "BPES", "cohort,", "respectively.", "One", "of", "the", "challenges", "of", "genetic", "testing", "in", "BPES", "is", "the", "establishment", "of", "genotype-phenotype", "correlations,", "mainly", "with", "respect", "to", "the", "ovarian", "phenotype.", "Genetic", "testing", "should", "be", "performed", "in", "the", "context", "of", "genetic", "counseling,", "however,", "and", "should", "be", "systematically", "complemented", "by", "a", "multidisciplinary", "clinical", "follow-up.", "Another", "challenge", "for", "health", "care", "professionals", "involved", "in", "BPES", "is", "the", "treatment", "of", "the", "eyelid", "phenotype", "and", "the", "prevention", "or", "treatment", "of", "POF." ]
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FOXL2 mutations and genomic rearrangements in BPES. The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF.
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7825576
[ "Autosomal", "dominant", "familial", "spastic", "paraplegia:", "reduction", "of", "the", "FSP1", " ", "candidate", "region", "on", "chromosome", "14q", "to", "7", "cM", "and", "locus", "heterogeneity.", "Three", "large", "pedigrees", "of", "German", "descent", "with", "autosomal", "dominant", "\"pure\"", "familial", "spastic", "paraplegia", "(FSP)", "were", "characterized", "clinically", "and", "genetically.", "Haplotype", "and", "linkage", "analyses,", "with", "microsatellites", "covering", "the", "FSP", "region", "on", "chromosome", "14q", "(locus", "FSP1", "),", "were", "performed.", "In", "pedigree", "W,", "we", "found", "a", "haplotype", "that", "cosegregates", "with", "the", "disease", "and", "observed", "three", "crossing-over", "events,", "reducing", "the", "FSP1", " ", "candidate", "region", "to", "7", "cM;", "in", "addition,", "the", "observation", "of", "apparent", "anticipation", "in", "this", "family", "suggests", "a", "trinucleotide", "repeat", "expansion", "as", "the", "mutation.", "In", "pedigrees", "D", "and", "S,", "the", "gene", "locus", "could", "be", "excluded", "from", "the", "whole", "FSP1", " ", "region,", "confirming", "the", "locus", "heterogeneity", "of", "autosomal", "dominant", "FSP." ]
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Autosomal dominant familial spastic paraplegia: reduction of the FSP1 candidate region on chromosome 14q to 7 cM and locus heterogeneity. Three large pedigrees of German descent with autosomal dominant "pure" familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1 ), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigrees D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP.
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11793474
[ "Integrating", "mutation", "data", "and", "structural", "analysis", "of", "the", "TP53", " ", "tumor-suppressor", "protein.", "TP53", " ", "encodes", "p53", ",", "which", "is", "a", "nuclear", "phosphoprotein", "with", "cancer-inhibiting", "properties.", "In", "response", "to", "DNA", "damage,", "p53", " ", "is", "activated", "and", "mediates", "a", "set", "of", "antiproliferative", "responses", "including", "cell-cycle", "arrest", "and", "apoptosis.", "Mutations", "in", "the", "TP53", " ", "gene", "are", "associated", "with", "more", "than", "50%", "of", "human", "cancers,", "and", "90%", "of", "these", "affect", "p53-DNA", "interactions,", "resulting", "in", "a", "partial", "or", "complete", "loss", "of", "transactivation", "functions.", "These", "mutations", "affect", "the", "structural", "integrity", "and/or", "p53", "-DNA", "interactions,", "leading", "to", "the", "partial", "or", "complete", "loss", "of", "the", "protein's", "function.", "We", "report", "here", "the", "results", "of", "a", "systematic", "automated", "analysis", "of", "the", "effects", "of", "p53", " ", "mutations", "on", "the", "structure", "of", "the", "core", "domain", "of", "the", "protein.", "We", "found", "that", "304", "of", "the", "882", "(34.4%)", "distinct", "mutations", "reported", "in", "the", "core", "domain", "can", "be", "explained", "in", "structural", "terms", "by", "their", "predicted", "effects", "on", "protein", "folding", "or", "on", "protein-DNA", "contacts.", "The", "proportion", "of", "\"explained\"", "mutations", "increased", "to", "55.6%", "when", "substitutions", "of", "evolutionary", "conserved", "amino", "acids", "were", "included.", "The", "automated", "method", "of", "structural", "analysis", "developed", "here", "may", "be", "applied", "to", "other", "frequently", "mutated", "gene", "mutations", "such", "as", "dystrophin,", "BRCA1", ",", "and", "G6PD", "dystrophin", ",", "BRCA1,", "and", "G6PD." ]
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Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein. TP53 encodes p53 , which is a nuclear phosphoprotein with cancer-inhibiting properties. In response to DNA damage, p53 is activated and mediates a set of antiproliferative responses including cell-cycle arrest and apoptosis. Mutations in the TP53 gene are associated with more than 50% of human cancers, and 90% of these affect p53-DNA interactions, resulting in a partial or complete loss of transactivation functions. These mutations affect the structural integrity and/or p53 -DNA interactions, leading to the partial or complete loss of the protein's function. We report here the results of a systematic automated analysis of the effects of p53 mutations on the structure of the core domain of the protein. We found that 304 of the 882 (34.4%) distinct mutations reported in the core domain can be explained in structural terms by their predicted effects on protein folding or on protein-DNA contacts. The proportion of "explained" mutations increased to 55.6% when substitutions of evolutionary conserved amino acids were included. The automated method of structural analysis developed here may be applied to other frequently mutated gene mutations such as dystrophin, BRCA1 , and G6PD dystrophin , BRCA1, and G6PD.
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16642441
[ "Association", "of", "polymorphisms", "in", "the", "Angiotensin-converting", "enzyme", " ", "gene", "with", "Alzheimer", "disease", "in", "an", "Israeli", "Arab", "community.", "Several", "lines", "of", "evidence", "support", "for", "a", "role", "of", "angiotensin", "converting", "enzyme", " ", "(", "ACE", ")", "in", "Alzheimer", "disease", "(AD).", "Most", "genetic", "studies", "have", "focused", "on", "an", "Alu", "insertion/deletion", "(I/D)", "polymorphism", "in", "the", "ACE", " ", "gene", "(", "DCP1", ")", "and", "have", "yielded", "conflicting", "results.", "We", "evaluated", "the", "association", "between", "15", "single-nucleotide", "polymorphisms", "(SNPs)", "in", "DCP1", ",", "including", "the", "I/D", "variant,", "and", "AD", "in", "a", "sample", "of", "92", "patients", "with", "AD", "and", "166", "nondemented", "controls", "from", "an", "inbred", "Israeli", "Arab", "community.", "Although", "there", "was", "no", "evidence", "for", "association", "between", "AD", "and", "I/D,", "we", "observed", "significant", "association", "with", "SNPs", "rs4343", "(P", "=", ".00001)", "and", "rs4351", "(P", "=", ".01).", "Haplotype", "analysis", "revealed", "remarkably", "significant", "evidence", "of", "association", "with", "the", "SNP", "combination", "rs4343", "and", "rs4351", "(global", "P", "=", "7.5", "x", "10(-7)).", "Individuals", "possessing", "the", "haplotype", "\"GA\"", "(frequency", "0.21", "in", "cases", "and", "0.01", "in", "controls)", "derived", "from", "these", "SNPs", "had", "a", "45-fold", "increased", "risk", "of", "developing", "AD", "(95%", "CI", "6.0-343.2)", "compared", "with", "those", "possessing", "any", "of", "the", "other", "three", "haplotypes.", "Longer", "range", "haplotypes", "including", "I/D", "were", "even", "more", "significant", "(lowest", "global", "P", "=", "1.1", "x", "10(-12)),", "but", "the", "only", "consistently", "associated", "alleles", "were", "in", "rs4343", "and", "rs4351.", "These", "results", "suggest", "that", "a", "variant", "in", "close", "proximity", "to", "rs4343", "and", "rs4351", "modulates", "susceptibility", "to", "AD", "in", "this", "community." ]
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Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community. Several lines of evidence support for a role of angiotensin converting enzyme ( ACE ) in Alzheimer disease (AD). Most genetic studies have focused on an Alu insertion/deletion (I/D) polymorphism in the ACE gene ( DCP1 ) and have yielded conflicting results. We evaluated the association between 15 single-nucleotide polymorphisms (SNPs) in DCP1 , including the I/D variant, and AD in a sample of 92 patients with AD and 166 nondemented controls from an inbred Israeli Arab community. Although there was no evidence for association between AD and I/D, we observed significant association with SNPs rs4343 (P = .00001) and rs4351 (P = .01). Haplotype analysis revealed remarkably significant evidence of association with the SNP combination rs4343 and rs4351 (global P = 7.5 x 10(-7)). Individuals possessing the haplotype "GA" (frequency 0.21 in cases and 0.01 in controls) derived from these SNPs had a 45-fold increased risk of developing AD (95% CI 6.0-343.2) compared with those possessing any of the other three haplotypes. Longer range haplotypes including I/D were even more significant (lowest global P = 1.1 x 10(-12)), but the only consistently associated alleles were in rs4343 and rs4351. These results suggest that a variant in close proximity to rs4343 and rs4351 modulates susceptibility to AD in this community.
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1550114
[ "Early", "British", "discoveries", "in", "human", "genetics:", "contributions", "of", "R.A.", "Fisher", "and", "J.B.S.", "Haldane", "to", "the", "development", "of", "blood", "groups." ]
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Early British discoveries in human genetics: contributions of R.A. Fisher and J.B.S. Haldane to the development of blood groups.
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21665002
[ "A", "congenital", "muscular", "dystrophy", "with", "mitochondrial", "structural", "abnormalities", "caused", "by", "defective", "de", "novo", "phosphatidylcholine", "biosynthesis.", "Congenital", "muscular", "dystrophy", "is", "a", "heterogeneous", "group", "of", "inherited", "muscle", "diseases", "characterized", "clinically", "by", "muscle", "weakness", "and", "hypotonia", "in", "early", "infancy.", "A", "number", "of", "genes", "harboring", "causative", "mutations", "have", "been", "identified,", "but", "several", "cases", "of", "congenital", "muscular", "dystrophy", "remain", "molecularly", "unresolved.", "We", "examined", "15", "individuals", "with", "a", "congenital", "muscular", "dystrophy", "characterized", "by", "early-onset", "muscle", "wasting,", "mental", "retardation,", "and", "peculiar", "enlarged", "mitochondria", "that", "are", "prevalent", "toward", "the", "periphery", "of", "the", "fibers", "but", "are", "sparse", "in", "the", "center", "on", "muscle", "biopsy,", "and", "we", "have", "identified", "homozygous", "or", "compound", "heterozygous", "mutations", "in", "the", "gene", "encoding", "choline", "kinase", "beta", " ", "(", "CHKB", ").", "This", "is", "the", "first", "enzymatic", "step", "in", "a", "biosynthetic", "pathway", "for", "phosphatidylcholine,", "the", "most", "abundant", "phospholipid", "in", "eukaryotes.", "In", "muscle", "of", "three", "affected", "individuals", "with", "nonsense", "mutations,", "choline", "kinase", "activities", "were", "undetectable,", "and", "phosphatidylcholine", "levels", "were", "decreased.", "We", "identified", "the", "human", "disease", "caused", "by", "disruption", "of", "a", "phospholipid", "de", "novo", "biosynthetic", "pathway,", "demonstrating", "the", "pivotal", "role", "of", "phosphatidylcholine", "in", "muscle", "and", "brain." ]
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A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta ( CHKB ). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.
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8981969
[ "Prevalence", "and", "parental", "origin", "of", "de", "novo", "RET", " ", "mutations", "in", "multiple", "endocrine", "neoplasia", "type", "2A", "and", "familial", "medullary", "thyroid", "carcinoma.", "Le", "Groupe", "d'Etude", "des", "Tumeurs", "a", "Calcitonine." ]
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Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine.
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11023809
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Major genes regulating total serum immunoglobulin E levels in families with asthma. Immunoglobulin E ( IgE Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.
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10486328
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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.
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20817137
[ "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." ]
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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.
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12474144
[ "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", "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." ]
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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 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.
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9973288
[ "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." ]
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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.
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9915936
[ "1998", "ASHG", "presidential", "address.", "Making", "genomic", "medicine", "a", "reality." ]
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1998 ASHG presidential address. Making genomic medicine a reality.
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11058905
[ "Six", "novel", "MEN1", " ", "gene", "mutations", "in", "sporadic", "parathyroid", "tumors.", "We", "report", "nine", "mutations", "of", "the", "multiple", "endocrine", "neoplasia", "type", "1", " ", "(", "MEN1", ")", "gene", "in", "sporadic", "parathyroid", "adenomas.", "Six", "of", "them", "have", "not", "previously", "been", "described:", "E60X", ",", "P32R", ",", "261delA", ",", "934+2T-->G", ",", "S443P", ",", "and", "1593insC", ".", "The", "tissue", "samples", "were", "initially", "submitted", "to", "LOH", "analysis", "at", "11q13", "followed", "by", "SSCP", "screening", "of", "LOH-positive", "samples.", "Mutations", "were", "identified", "by", "direct", "sequencing", "and", "subcloning.", "Three", "(", "E60X", ",", "P32R", ",", "and", "261delA", ")", "were", "in", "exon", "2,", "one", "(934+2bp)", "in", "the", "splice", "junction", "of", "exon", "5,", "one", "(", "S443P", ")", "in", "exon", "9,", "and", "one", "(", "1593insC", ")", "in", "exon", "10.", "The", "3", "mutations", "in", "exon", "2", "were", "associated", "with", "loss", "and/or", "creation", "of", "a", "restriction", "site.", "The", "corresponding", "germline", "sequence", "of", "the", "MEN1", " ", "gene", "was", "normal.", "Most", "mutations", "would", "likely", "result", "in", "a", "nonfunctional", "menin", "protein,", "and", "therefore", "in", "the", "loss", "of", "a", "tumor", "suppressor", "protein." ]
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Six novel MEN1 gene mutations in sporadic parathyroid tumors. We report nine mutations of the multiple endocrine neoplasia type 1 ( MEN1 ) gene in sporadic parathyroid adenomas. Six of them have not previously been described: E60X , P32R , 261delA , 934+2T-->G , S443P , and 1593insC . The tissue samples were initially submitted to LOH analysis at 11q13 followed by SSCP screening of LOH-positive samples. Mutations were identified by direct sequencing and subcloning. Three ( E60X , P32R , and 261delA ) were in exon 2, one (934+2bp) in the splice junction of exon 5, one ( S443P ) in exon 9, and one ( 1593insC ) in exon 10. The 3 mutations in exon 2 were associated with loss and/or creation of a restriction site. The corresponding germline sequence of the MEN1 gene was normal. Most mutations would likely result in a nonfunctional menin protein, and therefore in the loss of a tumor suppressor protein.
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8100466
[ "Detection", "of", "polymorphisms", "using", "thermal", "cycling", "with", "a", "single", "oligonucleotide", "on", "a", "DNA", "sequencing", "gel.", "A", "method", "is", "described", "for", "the", "detection", "of", "restriction", "fragment", "length", "polymorphisms", "(RFLPs)", "in", "single", "copy", "genes", "in", "mammalian", "cells", "using", "one", "5'-labelled", "oligonucleotide.", "This", "linear", "amplification", "(LA)", "method", "employs", "a", "single", "oligonucleotide", "as", "primer,", "which", "is", "extended", "by", "Taq", "DNA", "polymerase", "up", "to", "a", "restriction", "enzyme", "cleavage", "site.", "The", "products", "are", "arithmetically", "amplified", "by", "thermal", "cycling.", "The", "size", "of", "the", "products", "are", "determined", "by", "the", "sequence", "of", "the", "oligonucleotide", "and", "the", "position", "of", "the", "restriction", "enzyme", "cleavage", "site.", "Hence,", "an", "RFLP", "can", "be", "observed", "by", "measuring", "the", "size", "of", "the", "products.", "Polymorphisms", "which", "differ", "in", "size", "by", "a", "small", "number", "of", "base", "pairs,", "as", "are", "found", "in", "(CA)n", "repeats,", "are", "especially", "suitable", "for", "analysis", "by", "the", "LA", "procedure", "since", "the", "products", "are", "run", "on", "DNA", "sequencing", "gels.", "A", "number", "of", "genes", "were", "examined", "by", "the", "procedure", "and", "all", "produced", "a", "satisfactory", "signal", "including", "GC-rich", "template.", "It", "is", "proposed", "that", "the", "LA", "method", "would", "be", "suitable", "for", "large-scale", "genetic", "linkage", "analysis.", "The", "LA", "procedure", "has", "many", "advantages", "including", "the", "ability", "to", "multiplex", "signals", "under", "the", "same", "conditions,", "and", "lower", "cost", "since", "only", "one", "primer", "is", "needed." ]
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Detection of polymorphisms using thermal cycling with a single oligonucleotide on a DNA sequencing gel. A method is described for the detection of restriction fragment length polymorphisms (RFLPs) in single copy genes in mammalian cells using one 5'-labelled oligonucleotide. This linear amplification (LA) method employs a single oligonucleotide as primer, which is extended by Taq DNA polymerase up to a restriction enzyme cleavage site. The products are arithmetically amplified by thermal cycling. The size of the products are determined by the sequence of the oligonucleotide and the position of the restriction enzyme cleavage site. Hence, an RFLP can be observed by measuring the size of the products. Polymorphisms which differ in size by a small number of base pairs, as are found in (CA)n repeats, are especially suitable for analysis by the LA procedure since the products are run on DNA sequencing gels. A number of genes were examined by the procedure and all produced a satisfactory signal including GC-rich template. It is proposed that the LA method would be suitable for large-scale genetic linkage analysis. The LA procedure has many advantages including the ability to multiplex signals under the same conditions, and lower cost since only one primer is needed.
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19804848
[ "Familial", "hemophagocytic", "lymphohistiocytosis", "type", "5", "(FHL-5)", "is", "caused", "by", "mutations", "in", "Munc18-2", " ", "and", "impaired", "binding", "to", "syntaxin", "11.", "Rapid", "intracellular", "transport", "and", "secretion", "of", "cytotoxic", "granules", "through", "the", "immunological", "synapse", "requires", "a", "balanced", "interaction", "of", "several", "proteins.", "Disturbance", "of", "this", "highly", "regulated", "process", "underlies", "familial", "hemophagocytic", "lymphohistiocytosis", "(FHL),", "a", "genetically", "heterogeneous", "autosomal-recessive", "disorder", "characterized", "by", "a", "severe", "hyperinflammatory", "phenotype.", "Here,", "we", "have", "assigned", "FHL-5", "to", "a", "1", "Mb", "region", "on", "chromosome", "19p", "by", "using", "high-resolution", "SNP", "genotyping", "in", "eight", "unrelated", "FHL", "patients", "from", "consanguineous", "families.", "Subsequently,", "we", "found", "nine", "different", "mutations,", "either", "truncating", "or", "missense,", "in", "STXBP2", " ", "in", "twelve", "patients", "from", "Turkey,", "Saudi", "Arabia,", "and", "Central", "Europe.", "STXBP2", " ", "encodes", "syntaxin", "binding", "protein", "2", " ", "(", "Munc18-2", "),", "involved", "in", "the", "regulation", "of", "vesicle", "transport", "to", "the", "plasma", "membrane.", "We", "have", "identified", "syntaxin", "11", ",", "a", "SNARE", "protein", "mutated", "in", "FHL-4,", "as", "an", "interaction", "partner", "of", "STXBP2", ".", "This", "interaction", "is", "eliminated", "by", "the", "missense", "mutations", "found", "in", "our", "FHL-5", "patients,", "which", "leads", "to", "a", "decreased", "stability", "of", "both", "proteins,", "as", "shown", "in", "patient", "lymphocytes.", "Activity", "of", "natural", "killer", "and", "cytotoxic", "T", "cells", "was", "markedly", "reduced", "or", "absent,", "as", "determined", "by", "CD107", "degranulation.", "Our", "findings", "thus", "identify", "a", "key", "role", "for", "STXBP2", "FHL-5", " ", "to", "a", "1", "Mb", "region", "on", "chromosome", "19p", "by", "using", "high-resolution", "SNP", "genotyping", "in", "eight", "unrelated", "FHL", "patients", "from", "consanguineous", "families.", "Subsequently,", "we", "found", "nine", "different", "mutations,", "either", "truncating", "or", "missense,", "in", "STXBP2", "in", "twelve", "patients", "from", "Turkey,", "Saudi", "Arabia,", "and", "Central", "Europe.", "STXBP2", "encodes", "syntaxin", "binding", "protein", "2", "(Munc18-2),", "involved", "in", "the", "regulation", "of", "vesicle", "transport", "to", "the", "plasma", "membrane.", "We", "have", "identified", "syntaxin", "11,", "a", "SNARE", "protein", "mutated", "in", "FHL-4,", "as", "an", "interaction", "partner", "of", "STXBP2.", "This", "interaction", "is", "eliminated", "by", "the", "missense", "mutations", "found", "in", "our", "FHL-5", "FHL-4", "syntaxin", "11", ".", "Rapid", "intracellular", "transport", "and", "secretion", "of", "cytotoxic", "granules", "through", "the", "immunological", "synapse", "requires", "a", "balanced", "interaction", "of", "several", "proteins.", "Disturbance", "of", "this", "highly", "regulated", "process", "underlies", "familial", "hemophagocytic", "lymphohistiocytosis", "(FHL),", "a", "genetically", "heterogeneous", "autosomal-recessive", "disorder", "characterized", "by", "a", "severe", "hyperinflammatory", "phenotype.", "Here,", "we", "have", "assigned", "FHL-5", "to", "a", "1", "Mb", "region", "on", "chromosome", "19p", "by", "using", "high-resolution", "SNP", "genotyping", "in", "eight", "unrelated", "FHL", "patients", "from", "consanguineous", "families.", "Subsequently,", "we", "found", "nine", "different", "mutations,", "either", "truncating", "or", "missense,", "in", "STXBP2", "in", "twelve", "patients", "from", "Turkey,", "Saudi", "Arabia,", "and", "Central", "Europe.", "STXBP2", "encodes", "syntaxin", "binding", "protein", "2", "(Munc18-2),", "involved", "in", "the", "regulation", "of", "vesicle", "transport", "to", "the", "plasma", "membrane.", "We", "have", "identified", "syntaxin", "11,", "a", "SNARE", "protein", "mutated", "in", "FHL-4,", "as", "an", "interaction", "partner", "of", "STXBP2.", "This", "interaction", "is", "eliminated", "by", "the", "missense", "mutations", "found", "in", "our", "FHL-5", "patients,", "which", "leads", "to", "a", "decreased", "stability", "of", "both", "proteins,", "as", "shown", "in", "patient", "lymphocytes.", "Activity", "of", "natural", "killer", "and", "cytotoxic", "T", "cells", "was", "markedly", "reduced", "or", "absent,", "as", "determined", "by", "CD107", "degranulation.", "Our", "findings", "thus", "identify", "a", "key", "role", "for", "STXBP2", "in", "lytic", "granule", "exocytosis." ]
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Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 ( Munc18-2 ), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11 , a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2 . This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 FHL-4 syntaxin 11 . Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.
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21412943
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Novel C2orf71 mutations account for ∼1% of cases in a large French arRP cohort. Autosomal-recessive retinitis pigmentosa (arRP) is a genetically heterogeneous group of disorders to which a novel gene, C2orf71 , was recently associated. The purpose of our study was to establish the prevalence and nature of C2orf71 mutations in a clinically well-characterized cohort of 345 sporadic and arRP French cases. Direct sequencing of C2orf71 was performed in 209 subjects for whom mutations had previously been excluded by microarray technology and direct sequencing of EYS . Putative pathogenicity of the identified variants was evaluated through co-segregation analysis, screening of more than 188 control chromosomes and prediction programs. We identified two patients compound heterozygous for mutations predicted to lead to a premature stop codon, 3 of which are novel. In addition, 3 patients carried a single variant of likely pathogenicity. Furthermore a large number of novel putative non-disease causing variants were identified, highlighting the extremely polymorphic nature of C2orf71 . To our knowledge, our study provides the first large scale screening of C2orf71 in a French arRP cohort through direct sequencing and suggests that it would account for approximately 1% of arRP cases.
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17186465
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Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata. Detecting departures from Hardy-Weinberg equilibrium (HWE) of marker-genotype frequencies is a crucial first step in almost all human genetic analyses. When a sample is stratified by multiple ethnic groups, it is important to allow the marker-allele frequencies to differ over the strata. In this situation, it is common to test for HWE by using an exact test within each stratum and then using the minimum P value as a global test. This approach does not account for multiple testing, and, because it does not combine information over strata, it does not have optimal power. Several approximate methods to combine information over strata have been proposed, but most of them sum over strata a measure of departure from HWE; if the departures are in different directions, then summing can diminish the overall evidence of departure from HWE. An exact stratified test is more appealing because it uses the probability of genotype configurations across the strata as evidence for global departures from HWE. We developed an exact stratified test for HWE for diallelic markers, such as single-nucleotide polymorphisms (SNPs), and an exact test for homogeneity of Hardy-Weinberg disequilibrium. By applying our methods to data from Perlegen and HapMap--a combined total of more than five million SNP genotypes, with three to four strata and strata sizes ranging from 23 to 60 subjects--we illustrate that the exact stratified test provides more-robust and more-powerful results than those obtained by either the minimum of exact test P values over strata or approximate stratified tests that sum measures of departure from HWE. Hence, our new methods should be useful for samples composed of multiple ethnic groups.
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8651297
[ "Mutations", "and", "phenotype", "in", "isolated", "glycerol", "kinase", "deficiency.", "We", "demonstrate", "that", "isolated", "glycerol", "kinase", " ", "(", "GK", ")", "deficiency", "in", "three", "families", "results", "from", "mutation", "of", "the", "Xp21", "GK", " ", "gene.", "GK", " ", "mutations", "were", "detected", "in", "four", "patients", "with", "widely", "differing", "phenotypes.", "Patient", "1", "had", "a", "splice-site", "mutation", "causing", "premature", "termination.", "His", "general", "health", "was", "good", "despite", "absent", "GK", " ", "activity,", "indicating", "that", "isolated", "GK", " ", "deficiency", "can", "be", "silent.", "Patient", "2", "had", "GK", " ", "deficiency", "and", "a", "severe", "phenotype", "involving", "psychomotor", "retardation", "and", "growth", "delay,", "bone", "dysplasia,", "and", "seizures,", "similar", "to", "the", "severe", "phenotype", "of", "one", "of", "the", "first", "described", "cases", "of", "GK", "deficiency.", "His", "younger", "brother,", "patient", "3,", "also", "had", "GK", " ", "deficiency,", "but", "so", "far", "his", "development", "has", "been", "normal.", "GK", " ", "exon", "17", "was", "deleted", "in", "both", "brothers,", "implicating", "additional", "factors", "in", "causation", "of", "the", "severe", "phenotype", "of", "patient", "2.", "Patient", "4", "had", "both", "GK", "deficiency", "with", "mental", "retardation", "and", "a", "GK", "missense", "mutation", "(", "D440V", "GK", "GK", " ", "deficiency", "with", "mental", "retardation", "and", "a", "GK", "missense", "mutation", "(D440V).", "Possible", "explanations", "for", "the", "phenotypic", "variation", "of", "these", "four", "patients", "include", "ascertainment", "bias;", "metabolic", "or", "environmental", "stress", "as", "a", "precipitating", "factor", "in", "revealing", "GK-related", "changes,", "as", "has", "previously", "been", "described", "in", "juvenile", "GK", " ", "deficiency;", "and", "interactions", "with", "functional", "polymorphisms", "in", "other", "genes", "that", "alter", "the", "effect", "of", "GK", " ", "deficiency", "on", "normal", "development." ]
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Mutations and phenotype in isolated glycerol kinase deficiency. We demonstrate that isolated glycerol kinase ( GK ) deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated GK deficiency can be silent. Patient 2 had GK deficiency and a severe phenotype involving psychomotor retardation and growth delay, bone dysplasia, and seizures, similar to the severe phenotype of one of the first described cases of GK deficiency. His younger brother, patient 3, also had GK deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors in causation of the severe phenotype of patient 2. Patient 4 had both GK deficiency with mental retardation and a GK missense mutation ( D440V GK GK deficiency with mental retardation and a GK missense mutation (D440V). Possible explanations for the phenotypic variation of these four patients include ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as has previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development.
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16252233
[ "High-resolution", "identification", "of", "chromosomal", "abnormalities", "using", "oligonucleotide", "arrays", "containing", "116,204", "SNPs.", "Mutation", "of", "the", "human", "genome", "ranges", "from", "single", "base-pair", "changes", "to", "whole-chromosome", "aneuploidy.", "Karyotyping,", "fluorescence", "in", "situ", "hybridization,", "and", "comparative", "genome", "hybridization", "are", "currently", "used", "to", "detect", "chromosome", "abnormalities", "of", "clinical", "significance.", "These", "methods,", "although", "powerful,", "suffer", "from", "limitations", "in", "speed,", "ease", "of", "use,", "and", "resolution,", "and", "they", "do", "not", "detect", "copy-neutral", "chromosomal", "aberrations--for", "example,", "uniparental", "disomy", "(UPD).", "We", "have", "developed", "a", "high-throughput", "approach", "for", "assessment", "of", "DNA", "copy-number", "changes,", "through", "use", "of", "high-density", "synthetic", "oligonucleotide", "arrays", "containing", "116,204", "single-nucleotide", "polymorphisms,", "spaced", "at", "an", "average", "distance", "of", "23.6", "kb", "across", "the", "genome.", "Using", "this", "approach,", "we", "analyzed", "samples", "that", "failed", "conventional", "karyotypic", "analysis,", "and", "we", "detected", "amplifications", "and", "deletions", "across", "a", "wide", "range", "of", "sizes", "(1.3-145.9", "Mb),", "identified", "chromosomes", "containing", "anonymous", "chromatin,", "and", "used", "genotype", "data", "to", "determine", "the", "molecular", "origin", "of", "two", "cases", "of", "UPD.", "Furthermore,", "our", "data", "provided", "independent", "confirmation", "for", "a", "case", "that", "had", "been", "misinterpreted", "by", "karyotype", "analysis.", "The", "high", "resolution", "of", "our", "approach", "provides", "more-precise", "breakpoint", "mapping,", "which", "allows", "subtle", "phenotypic", "heterogeneity", "to", "be", "distinguished", "at", "a", "molecular", "level.", "The", "accurate", "genotype", "information", "provided", "on", "these", "arrays", "enables", "the", "identification", "of", "copy-neutral", "loss-of-heterozygosity", "events,", "and", "the", "minimal", "requirement", "of", "DNA", "(250", "ng", "per", "array)", "allows", "rapid", "analysis", "of", "samples", "without", "the", "need", "for", "cell", "culture.", "This", "technology", "overcomes", "many", "limitations", "currently", "encountered", "in", "routine", "clinical", "diagnostic", "laboratories", "tasked", "with", "accurate", "and", "rapid", "diagnosis", "of", "chromosomal", "abnormalities." ]
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High-resolution identification of chromosomal abnormalities using oligonucleotide arrays containing 116,204 SNPs. Mutation of the human genome ranges from single base-pair changes to whole-chromosome aneuploidy. Karyotyping, fluorescence in situ hybridization, and comparative genome hybridization are currently used to detect chromosome abnormalities of clinical significance. These methods, although powerful, suffer from limitations in speed, ease of use, and resolution, and they do not detect copy-neutral chromosomal aberrations--for example, uniparental disomy (UPD). We have developed a high-throughput approach for assessment of DNA copy-number changes, through use of high-density synthetic oligonucleotide arrays containing 116,204 single-nucleotide polymorphisms, spaced at an average distance of 23.6 kb across the genome. Using this approach, we analyzed samples that failed conventional karyotypic analysis, and we detected amplifications and deletions across a wide range of sizes (1.3-145.9 Mb), identified chromosomes containing anonymous chromatin, and used genotype data to determine the molecular origin of two cases of UPD. Furthermore, our data provided independent confirmation for a case that had been misinterpreted by karyotype analysis. The high resolution of our approach provides more-precise breakpoint mapping, which allows subtle phenotypic heterogeneity to be distinguished at a molecular level. The accurate genotype information provided on these arrays enables the identification of copy-neutral loss-of-heterozygosity events, and the minimal requirement of DNA (250 ng per array) allows rapid analysis of samples without the need for cell culture. This technology overcomes many limitations currently encountered in routine clinical diagnostic laboratories tasked with accurate and rapid diagnosis of chromosomal abnormalities.
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1373934
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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.
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8488836
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Rapid prenatal diagnosis of chromosomal aneuploidies by fluorescence in situ hybridization: clinical experience with 4,500 specimens. Detection of chromosome aneuploidies in uncultured amniocytes is possible using fluorescence in situ hybridization (FISH). We herein describe the results of the first clinical program which utilized FISH for the rapid detection of chromosome aneuploidies in uncultured amniocytes. FISH was performed on physician request, as an adjunct to cytogenetics in 4,500 patients. Region-specific DNA probes to chromosomes 13, 18, 21, X, and Y were used to determine ploidy by analysis of signal number in hybridized nuclei. A sample was considered to be euploid when all autosomal probes generated two hybridization signals and when a normal sex chromosome pattern was observed in greater than or equal to 80% of hybridized nuclei. A sample was considered to be aneuploid when greater than or equal to 70% of hybridized nuclei displayed the same abnormal hybridization pattern for a specific probe. Of the attempted analyses, 90.2% met these criteria and were reported as informative to referring physicians within 2 d of receipt. Based on these reporting parameters, the overall detection rate for aneuploidies was 73.3% (107/146), with an accuracy of informative results for aneuploidies of 93.9% (107/114). Compared to cytogenetics, the accuracy of all informative FISH results, euploid and aneuploid, was 99.8%, and the specificity was 99.9%. In those pregnancies where fetal abnormalities had been observed by ultrasound, referring physicians requested FISH plus cytogenetics at a significantly higher rate than they requested cytogenetics alone. The current prenatal FISH protocol is not designed to detect all chromosome abnormalities and should only be utilized as an adjunctive test to cytogenetics. This experience demonstrates that FISH can provide a rapid and accurate clinical method for prenatal identification of chromosome aneuploidies.
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20333758
[ "Functional", "analysis", "of", "mutations", "in", "the", "ATP", "loop", "of", "the", "Wilson", "disease", "copper", "transporter,", "ATP7B", ".", "Wilson", "disease", "(WND)", "is", "an", "autosomal", "recessive", "disorder", "resulting", "from", "mutation", "of", "ATP7B", ".", "Transport", "of", "copper", "by", "ATP7B", " ", "from", "the", "trans-Golgi", "of", "hepatocytes", "into", "apical", "membrane-trafficked", "vesicles", "for", "excretion", "in", "the", "bile", "is", "the", "major", "means", "of", "copper", "elimination", "from", "the", "body.", "Although", "copper", "is", "an", "essential", "nutrient,", "homeostasis", "must", "be", "carefully", "maintained.", "If", "homeostasis", "is", "disrupted,", "copper", "can", "accumulate", "within", "the", "liver,", "kidney,", "cornea,", "and/or", "brain.", "The", "range", "of", "organs", "affected", "leads", "to", "clinical", "heterogeneity", "and", "difficulty", "in", "WND", "diagnosis.", "Sequencing", "of", "ATP7B", " ", "is", "an", "important", "adjunct", "for", "diagnosis", "but", "has", "led", "to", "the", "discovery", "of", "many", "novel", "missense", "variants.", "Although", "prediction", "programs", "are", "available,", "functional", "characterization", "is", "essential", "for", "determining", "the", "consequence", "of", "novel", "variants.", "We", "have", "tested", "12", "missense", "variants", "localized", "to", "the", "ATP", "loop", "of", "ATP7B", " ", "and", "compared", "three", "predictive", "programs", "(SIFT,", "PolyPhen,", "and", "Align-GVGD).", "We", "found", "p.L1043P", ",", "p.G1000R", ",", "p.G1101R", ",", "p.I1102T", ",", "p.V1239G", ",", "and", "p.D1267V", " ", "deleterious;", "p.G1176E", " ", "and", "p.G1287S", " ", "intermediate;", "p.E1173G", " ", "temperature", "sensitive;", "p.T991M", " ", "and", "p.I1148T", " ", "mild;", "and", "p.R1228T", " ", "functioning", "as", "wild", "type.", "We", "found", "that", "SIFT", "most", "often", "agreed", "with", "functional", "data", "(92%),", "compared", "with", "PolyPhen", "(83%)", "and", "Align-GVGD", "(67%).", "We", "conclude", "that", "variants", "found", "to", "negatively", "affect", "function", "likely", "contribute", "to", "the", "WND", "phenotype", "in", "patients." ]
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Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B . Wilson disease (WND) is an autosomal recessive disorder resulting from mutation of ATP7B . Transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body. Although copper is an essential nutrient, homeostasis must be carefully maintained. If homeostasis is disrupted, copper can accumulate within the liver, kidney, cornea, and/or brain. The range of organs affected leads to clinical heterogeneity and difficulty in WND diagnosis. Sequencing of ATP7B is an important adjunct for diagnosis but has led to the discovery of many novel missense variants. Although prediction programs are available, functional characterization is essential for determining the consequence of novel variants. We have tested 12 missense variants localized to the ATP loop of ATP7B and compared three predictive programs (SIFT, PolyPhen, and Align-GVGD). We found p.L1043P , p.G1000R , p.G1101R , p.I1102T , p.V1239G , and p.D1267V deleterious; p.G1176E and p.G1287S intermediate; p.E1173G temperature sensitive; p.T991M and p.I1148T mild; and p.R1228T functioning as wild type. We found that SIFT most often agreed with functional data (92%), compared with PolyPhen (83%) and Align-GVGD (67%). We conclude that variants found to negatively affect function likely contribute to the WND phenotype in patients.
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17024664
[ "Genotype-phenotype", "correlations", "in", "von", "Hippel-Lindau", "disease.", "von", "Hippel-Lindau", "(VHL)", "disease", "is", "a", "dominantly", "inherited", "familial", "cancer", "syndrome", "resulting", "from", "mutations", "in", "the", "VHL", "tumor", "suppressor", "gene.", "VHL", "disease", "displays", "marked", "variation", "in", "expression", "and", "the", "presence", "of", "pheochromocytoma", "has", "been", "linked", "to", "missense", "VHL", "mutations.", "We", "analyzed", "genotype-phenotype", "correlations", "in", "573", "individuals", "with", "VHL", "disease.", "Routine", "clinical", "and", "radiological", "surveillance", "of", "VHL", "patients", "and", "at-risk", "relatives", "was", "associated", "with", "increased", "detection", "of", "retinal", "angiomatosis", "(73", "vs.", "59%", "of", "cases)", "and", "a", "reduction", "in", "age", "at", "diagnosis", "of", "renal", "cell", "carcinoma", "(RCC)", "(44.0+/-10.9", "vs.", "39.7+/-10.3", "years).", "We", "confirmed", "the", "association", "of", "pheochromocytoma", "with", "missense", "mutations", "described", "previously,", "but", "stratifying", "missense", "mutations", "into", "those", "that", "resulted", "in", "substitution", "of", "a", "surface", "amino", "acid", "and", "those", "that", "disrupted", "structural", "integrity", "demonstrated", "that", "surface", "amino", "acid", "substitutions", "conferred", "a", "higher", "pheochromocytoma", "risk.", "Age", "at", "first", "manifestation", "of", "VHL", "disease", "was", "significantly", "earlier", "(P=0.001),", "and", "age-related", "risks", "of", "retinal", "angiomas", "and", "RCC", "were", "higher", "(P=0.022", "and", "P=0.0008,", "respectively)", "in", "individuals", "with", "a", "nonsense", "or", "frameshift", "mutation", "than", "in", "those", "with", "deletions", "or", "missense", "mutations", "that", "disrupted", "the", "structural", "integrity", "of", "the", "VHL", "gene", "product", "(pVHL).", "These", "results", "extend", "genotype-phenotype-protein", "structure", "correlations", "in", "VHL", "disease", "and", "provide", "a", "baseline", "for", "future", "chemoprevention", "studies", "in", "VHL", "disease." ]
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Genotype-phenotype correlations in von Hippel-Lindau disease. von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene. VHL disease displays marked variation in expression and the presence of pheochromocytoma has been linked to missense VHL mutations. We analyzed genotype-phenotype correlations in 573 individuals with VHL disease. Routine clinical and radiological surveillance of VHL patients and at-risk relatives was associated with increased detection of retinal angiomatosis (73 vs. 59% of cases) and a reduction in age at diagnosis of renal cell carcinoma (RCC) (44.0+/-10.9 vs. 39.7+/-10.3 years). We confirmed the association of pheochromocytoma with missense mutations described previously, but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk. Age at first manifestation of VHL disease was significantly earlier (P=0.001), and age-related risks of retinal angiomas and RCC were higher (P=0.022 and P=0.0008, respectively) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product (pVHL). These results extend genotype-phenotype-protein structure correlations in VHL disease and provide a baseline for future chemoprevention studies in VHL disease.
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12515255
[ "The", "ABCA4", " ", "gene", "in", "autosomal", "recessive", "cone-rod", "dystrophies." ]
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The ABCA4 gene in autosomal recessive cone-rod dystrophies.
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22570304
[ "Retinitis", "pigmentosa:", "More", "genes,", "more", "variants,", "more", "work." ]
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Retinitis pigmentosa: More genes, more variants, more work.
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Mutations and DNA diagnoses of classical citrullinemia. Classical citrullinemia is an autosomal recessive disease caused by a genetic deficiency of argininosuccinate synthetase (ASS). We have previously identified 20 mutations in ASS mRNA of human classical citrullinemia and already established the DNA diagnosis of seven mutations as follows. By Southern blot analysis, each of the alleles with exon 5 or 6 deletion in mRNA appears to involve deletion of genomic DNA from this region. Five mutations involving R304W , G324S , IVS-6(-2) (delta Ex7), IVS-13(+5) IVS-6(-2) (delta Ex7), IVS-13(+5) (delta Ex13), and delta 13 bp/Ex15&IVS-15 (ins37 b/Ex15&16) are diagnosed by a combination of PCR (or modified PCR) and restriction enzyme digestion. It is important to identify the mutation in genomic DNA for prenatal diagnosis and carrier detection. In the present study, we report a novel missense mutation ( R279Q ) and a new abnormality in the ASS gene ( delta 11 bp/IVS-15 ). As three missense mutations ( R272C , R279Q , and G280R ) were found in exon 12, we isolated and sequenced the intron regions surrounding exon 12 to establish a DNA diagnostic test. Although a mutation with a deletion of the first seven bases in exon 16 of mRNA ( delta 7 b/Ex16 ) was found in both Japanese and American patients, the abnormality on the ASS deletion of the first seven bases in exon 16 of mRNA (delta 7 b/Ex16) was found in both Japanese and American patients, the abnormality on the ASS gene was different between the Japanese allele ( delta 11 bp/IVS-15 ) and American allele ( IVS-15(-1) ins37 b/Ex15&16 ) are diagnosed by a combination of PCR (or modified PCR) and restriction enzyme digestion. It is important to identify the mutation in genomic DNA for prenatal diagnosis and carrier detection. In the present study, we report a novel missense mutation (R279Q) and a new abnormality in the ASS gene (delta 11 bp/IVS-15). As three missense mutations (R272C, R279Q, and G280R) were found in exon 12, we isolated and sequenced the intron regions surrounding exon 12 to establish a DNA diagnostic test. Although a mutation with a deletion of the first seven bases in exon 16 of mRNA (delta 7 b/Ex16) was found in both Japanese and American patients, the abnormality on the ASS gene was different between the Japanese allele (delta 11 bp/IVS-15) and American allele (IVS-15(-1)). The DNA diagnosis of 47 Japanese alleles with classical citrullinemia showed that the IVS-6(-2) and R304W mutations were found in 49% and 17% of the mutated alleles, respectively. We now have DNA diagnosis systems to detect 14 out of 22 mutations and are performing prenatal diagnosis and carrier detection using genomic DNA on classical citrullinemia.
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7977360
[ "Molecular", "characterization", "of", "de", "novo", "secondary", "trisomy", "13.", "Unbalanced", "Robertsonian", "translocations", "are", "a", "significant", "cause", "of", "mental", "retardation", "and", "fetal", "wastage.", "The", "majority", "of", "homologous", "rearrangements", "of", "chromosome", "21", "in", "Down", "syndrome", "have", "been", "shown", "to", "be", "isochromosomes.", "Aside", "from", "chromosome", "21,", "very", "little", "is", "known", "about", "other", "acrocentric", "homologous", "rearrangements.", "In", "this", "study,", "four", "cases", "of", "de", "novo", "secondary", "trisomy", "13", "are", "presented.", "FISH", "using", "alpha-satellite", "sequences,", "rDNA,", "and", "a", "pTRI-6", "satellite", "I", "sequence", "specific", "to", "the", "short", "arm", "of", "chromosome", "13", "showed", "all", "four", "rearrangements", "to", "be", "dicentric", "and", "apparently", "devoid", "of", "ribosomal", "genes.", "Three", "of", "four", "rearrangements", "retained", "the", "pTRI-6", "satellite", "I", "sequence.", "Case", "1", "was", "the", "exception,", "showing", "a", "deletion", "of", "this", "sequence", "in", "the", "rearrangement,", "although", "both", "parental", "chromosomes", "13", "had", "strong", "positive", "hybridization", "signals.", "Eleven", "microsatellite", "markers", "from", "chromosome", "13", "were", "also", "used", "to", "characterize", "the", "rearrangements.", "Of", "the", "four", "possible", "outcomes,", "one", "maternal", "Robertsonian", "translocation,", "two", "paternal", "isochromosomes,", "and", "one", "maternal", "isochromosome", "were", "observed.", "A", "double", "recombination", "was", "observed", "in", "the", "maternally", "derived", "rob(13q13q).", "No", "recombination", "events", "were", "detected", "in", "any", "isochromosome.", "The", "parental", "origins", "and", "molecular", "chromosomal", "structure", "of", "these", "cases", "are", "compared", "with", "previous", "studies", "of", "de", "novo", "acrocentric", "rearrangements." ]
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Molecular characterization of de novo secondary trisomy 13. Unbalanced Robertsonian translocations are a significant cause of mental retardation and fetal wastage. The majority of homologous rearrangements of chromosome 21 in Down syndrome have been shown to be isochromosomes. Aside from chromosome 21, very little is known about other acrocentric homologous rearrangements. In this study, four cases of de novo secondary trisomy 13 are presented. FISH using alpha-satellite sequences, rDNA, and a pTRI-6 satellite I sequence specific to the short arm of chromosome 13 showed all four rearrangements to be dicentric and apparently devoid of ribosomal genes. Three of four rearrangements retained the pTRI-6 satellite I sequence. Case 1 was the exception, showing a deletion of this sequence in the rearrangement, although both parental chromosomes 13 had strong positive hybridization signals. Eleven microsatellite markers from chromosome 13 were also used to characterize the rearrangements. Of the four possible outcomes, one maternal Robertsonian translocation, two paternal isochromosomes, and one maternal isochromosome were observed. A double recombination was observed in the maternally derived rob(13q13q). No recombination events were detected in any isochromosome. The parental origins and molecular chromosomal structure of these cases are compared with previous studies of de novo acrocentric rearrangements.
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9545410
[ "A", "gene", "for", "familial", "juvenile", "polyposis", "maps", "to", "chromosome", "18q21.1.", "Familial", "juvenile", "polyposis", "(FJP)", "is", "a", "hamartomatouspolyposis", "syndrome", "in", "which", "affected", "family", "members", "develop", "upper", "and", "lower", "gastrointestinal", "juvenile", "polyps", "and", "are", "at", "increased", "risk", "for", "gastrointestinal", "cancer.", "A", "genetic", "locus", "for", "FJP", "has", "not", "yet", "been", "identified", "by", "linkage;", "therefore,", "the", "objective", "of", "this", "study", "was", "to", "perform", "a", "focused", "genome", "screen", "in", "a", "large", "family", "segregating", "FJP.", "No", "evidence", "for", "linkage", "was", "found", "with", "markers", "near", "MSH2,", " ", "MLH1,", " ", "MCC,", " ", "APC,", " ", "HMPS,", " ", "CDKN2A,", " ", "JP1,", " ", "PTEN,", " ", "KRAS2,", " ", "TP53,", " ", "or", "LKB1.", " ", "Linkage", "to", "FJP", "was", "established", "with", "several", "markers", "from", "chromosome", "18q21.1.", "The", "maximum", "LOD", "score", "was", "5.00,", "with", "marker", "D18S1099", "(recombination", "fraction", "of", ".001).", "Analysis", "of", "critical", "recombinants", "places", "the", "FJP", "gene", "in", "an", "11.9-cM", "interval", "bounded", "by", "D18S1118", "and", "D18S487,", "a", "region", "that", "also", "contains", "the", "tumor-suppressor", "genes", "DCC", " ", "and", "DPC4.", " ", "These", "data", "demonstrate", "localization", "of", "a", "gene", "for", "FJP", "to", "chromosome", "18q21.1", "by", "linkage,", "and", "they", "raise", "the", "possibility", "that", "either", "DCC", " ", "or", "DPC4", " ", "could", "be", "responsible", "for", "FJP." ]
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A gene for familial juvenile polyposis maps to chromosome 18q21.1. Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.
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12717633
[ "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." ]
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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.
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21412953
[ "Breakage-fusion-bridge", "cycles", "leading", "to", "inv", "dup", "del", "occur", "in", "human", "cleavage", "stage", "embryos.", "Recently,", "a", "high", "incidence", "of", "chromosome", "instability", "(CIN)", "was", "reported", "in", "human", "cleavage", "stage", "embryos.", "Based", "on", "the", "copy", "number", "changes", "that", "were", "observed", "in", "the", "blastomeres", "it", "was", "hypothesized", "that", "chromosome", "breakages", "and", "fusions", "occur", "frequently", "in", "cleavage", "stage", "human", "embryos", "and", "instigate", "subsequent", "breakage-fusion-bridge", "cycles.", "In", "addition,", "it", "was", "hypothesized", "that", "the", "DNA", "breaks", "present", "in", "spermatozoa", "could", "trigger", "this", "CIN.", "To", "test", "these", "hypotheses,", "we", "genotyped", "both", "parents", "as", "well", "as", "93", "blastomeres", "from", "24", "IVF", "embryos", "and", "developed", "a", "novel", "single", "nucleotide", "polymorphism", "(SNP)", "array-based", "algorithm", "to", "determine", "the", "parental", "origin", "of", "(aberrant)", "loci", "in", "single", "cells.", "Paternal", "as", "well", "as", "maternal", "alleles", "were", "commonly", "rearranged", "in", "the", "blastomeres", "indicating", "that", "sperm-specific", "DNA", "breaks", "do", "not", "explain", "the", "majority", "of", "these", "structural", "variants.", "The", "parent-of-origin", "analyses", "together", "with", "microarray-guided", "FISH", "analyses", "demonstrate", "the", "presence", "of", "inv", "dup", "del", "chromosomes", "as", "well", "as", "more", "complex", "rearrangements.", "These", "data", "provide", "unequivocal", "evidence", "for", "breakage-fusion-bridge", "cycles", "in", "those", "embryos", "and", "suggest", "that", "the", "human", "cleavage", "stage", "embryo", "is", "a", "major", "source", "of", "chromosomal", "disorders." ]
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Breakage-fusion-bridge cycles leading to inv dup del occur in human cleavage stage embryos. Recently, a high incidence of chromosome instability (CIN) was reported in human cleavage stage embryos. Based on the copy number changes that were observed in the blastomeres it was hypothesized that chromosome breakages and fusions occur frequently in cleavage stage human embryos and instigate subsequent breakage-fusion-bridge cycles. In addition, it was hypothesized that the DNA breaks present in spermatozoa could trigger this CIN. To test these hypotheses, we genotyped both parents as well as 93 blastomeres from 24 IVF embryos and developed a novel single nucleotide polymorphism (SNP) array-based algorithm to determine the parental origin of (aberrant) loci in single cells. Paternal as well as maternal alleles were commonly rearranged in the blastomeres indicating that sperm-specific DNA breaks do not explain the majority of these structural variants. The parent-of-origin analyses together with microarray-guided FISH analyses demonstrate the presence of inv dup del chromosomes as well as more complex rearrangements. These data provide unequivocal evidence for breakage-fusion-bridge cycles in those embryos and suggest that the human cleavage stage embryo is a major source of chromosomal disorders.
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8019556
[ "Mutations", "in", "PAX3", " ", "associated", "with", "Waardenburg", "syndrome", "type", "I.", "Waardenburg", "syndrome", "(WS)", "types", "I,", "II,", "and", "III", "(McKusick", "#14882,", "#19351,", "and", "#19350)", "are", "related", "autosomal", "dominant", "disorders", "characterized", "by", "sensorineural", "hearing", "loss,", "dystopia", "canthorum,", "pigmentary", "disturbances,", "and", "other", "developmental", "defects.", "Disease", "causing", "PAX3", " ", "mutations", "have", "been", "identified", "in", "a", "few", "families", "from", "each", "of", "the", "three", "disease", "subtypes,", "WS-I,", "WS-II,", "and", "WS-III.", "In", "others,", "although", "the", "mutations", "have", "not", "been", "pinpointed,", "linkage", "with", "the", "PAX3", " ", "locus", "on", "chromosome", "2q35", "has", "been", "demonstrated.", "The", "PAX3", " ", "protein", "is", "a", "transcription", "factor", "that", "contains", "both", "a", "paired-domain", "and", "a", "homeodomain", "DNA", "binding", "motif", "and", "appears", "to", "play", "a", "key", "role", "during", "embryogenesis.", "In", "this", "report,", "we", "describe", "two", "mutations", "in", "the", "human", "PAX3", " ", "gene", "that", "cause", "WS", "type", "I.", "One", "mutation", "is", "a", "deletion/frameshift", "in", "the", "paired-domain", "of", "PAX3", " ", "and", "results", "in", "a", "protein", "without", "functional", "DNA", "binding", "domains.", "The", "second", "mutation", "is", "a", "single-base", "substitution", "and", "results", "in", "a", "premature", "termination", "codon", "in", "the", "homeodomain", "of", "PAX3", ".", "This", "is", "the", "first", "demonstration", "of", "a", "mutation", "in", "the", "homeodomain", "DNA", "binding", "motif", "in", "this", "protein", "resulting", "in", "WS", "and", "one", "of", "the", "few", "examples", "of", "a", "mutation", "in", "a", "homeodomain", "of", "any", "protein", "that", "results", "in", "human", "disease." ]
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Mutations in PAX3 associated with Waardenburg syndrome type I. Waardenburg syndrome (WS) types I, II, and III (McKusick #14882, #19351, and #19350) are related autosomal dominant disorders characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Disease causing PAX3 mutations have been identified in a few families from each of the three disease subtypes, WS-I, WS-II, and WS-III. In others, although the mutations have not been pinpointed, linkage with the PAX3 locus on chromosome 2q35 has been demonstrated. The PAX3 protein is a transcription factor that contains both a paired-domain and a homeodomain DNA binding motif and appears to play a key role during embryogenesis. In this report, we describe two mutations in the human PAX3 gene that cause WS type I. One mutation is a deletion/frameshift in the paired-domain of PAX3 and results in a protein without functional DNA binding domains. The second mutation is a single-base substitution and results in a premature termination codon in the homeodomain of PAX3 . This is the first demonstration of a mutation in the homeodomain DNA binding motif in this protein resulting in WS and one of the few examples of a mutation in a homeodomain of any protein that results in human disease.
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9326327
[ "Molecular", "definition", "of", "22q11", "deletions", "in", "151", "velo-cardio-facial", "syndrome", "patients.", "Velo-cardio-facial", "syndrome", "(VCFS)", "is", "a", "relatively", "common", "developmental", "disorder", "characterized", "by", "craniofacial", "anomalies", "and", "conotruncal", "heart", "defects.", "Many", "VCFS", "patients", "have", "hemizygous", "deletions", "for", "a", "part", "of", "22q11,", "suggesting", "that", "haploinsufficiency", "in", "this", "region", "is", "responsible", "for", "its", "etiology.", "Because", "most", "cases", "of", "VCFS", "are", "sporadic,", "portions", "of", "22q11", "may", "be", "prone", "to", "rearrangement.", "To", "understand", "the", "molecular", "basis", "for", "chromosomal", "deletions,", "we", "defined", "the", "extent", "of", "the", "deletion,", "by", "genotyping", "151", "VCFS", "patients", "and", "performing", "haplotype", "analysis", "on", "105,", "using", "15", "consecutive", "polymorphic", "markers", "in", "22q11.", "We", "found", "that", "83%", "had", "a", "deletion", "and", ">90%", "of", "these", "had", "a", "similar", "approximately", "3", "Mb", "deletion,", "suggesting", "that", "sequences", "flanking", "the", "common", "breakpoints", "are", "susceptible", "to", "rearrangement.", "We", "found", "no", "correlation", "between", "the", "presence", "or", "size", "of", "the", "deletion", "and", "the", "phenotype.", "To", "further", "define", "the", "chromosomal", "breakpoints", "among", "the", "VCFS", "patients,", "we", "developed", "somatic", "hybrid", "cell", "lines", "from", "a", "set", "of", "VCFS", "patients.", "An", "11-kb", "resolution", "physical", "map", "of", "a", "1,080-kb", "region", "that", "includes", "deletion", "breakpoints", "was", "constructed,", "incorporating", "genes", "and", "expressed", "sequence", "tags", "(ESTs)", "isolated", "by", "the", "hybridization", "selection", "method.", "The", "ordered", "markers", "were", "used", "to", "examine", "the", "two", "separated", "copies", "of", "chromosome", "22", "in", "the", "somatic", "hybrid", "cell", "lines.", "In", "some", "cases,", "we", "were", "able", "to", "map", "the", "chromosome", "breakpoints", "within", "a", "single", "cosmid.", "A", "480-kb", "critical", "region", "for", "VCFS", "has", "been", "delineated,", "including", "the", "genes", "for", "GSCL,", " ", "CTP,", " ", "CLTD,", " ", "HIRA,", " ", "and", "TMVCF,", " ", "as", "well", "as", "a", "number", "of", "novel", "ordered", "ESTs." ]
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Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.
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11781875
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2001 ASHG Award for Excellence in Education. Introductory speech for Charles Scriver.
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Functional characterization of ryanodine receptor ( RYR1 ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. Mutations in the RYR1 gene are linked to malignant hyperthermia (MH), central core disease and multi-minicore disease. We screened by DHPLC the RYR1 gene in 24 subjects for mutations, and characterized functional alterations caused by some RYR1 variants. Three novel sequence variants and twenty novel polymorphisms were identified. Immortalized lymphoblastoid cell lines from patients with RYR1 variants and from controls were stimulated with 4-chloro-m-cresol (4-CmC) and the rate of extracellular acidification was recorded. We demonstrate that the increased acidification rate of lymphoblastoid cells in response to 4-CmC is mainly due to RYR1 activation. Cells expressing RYR1 variants in the N-terminal and in the central region of the protein ( p.Arg530His , p.Arg2163Pro , p.Asn2342Ser , p.Glu2371Gly and p.Arg2454His ) displayed higher activity compared with controls; this could account for the MH-susceptible phenotype. Cell lines harboring RYR1( Cys4664Arg RYR1 (Cys4664Arg) were significantly less activated by 4-CmC. This result indicates that the p.Cys4664Arg variant causes a leaky channel and depletion of intracellular stores. The functional changes detected corroborate the variants analyzed as disease-causing alterations and the acidification rate measurements as a means to monitor Ca(2+)-induced metabolic changes in cells harboring mutant RYR1 p.Cys4664Arg variant causes a leaky channel and depletion of intracellular stores. The functional changes detected corroborate the variants analyzed as disease-causing alterations and the acidification rate measurements as a means to monitor Ca(2+)-induced metabolic changes in cells harboring mutant RYR1 channels.
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19836010
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Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. We report recessive mutations in the gene for the latent transforming growth factor-beta binding protein 4 ( LTBP4 ) in four unrelated patients with a human syndrome disrupting pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the four patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis, enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Four of the five identified LTBP4 mutations led to premature termination of translation and destabilization of the LTBP4 LTBP4 mutations led to premature termination of translation and destabilization of the LTBP4 mRNA. Impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased transforming growth factor-beta ( TGF-beta ) activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by the disease. These molecular defects were associated with blocked alveolarization and airway collapse in the lung. Our results show that coupling of TGF-beta signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems by multifunctional proteins such as LTBP4 .
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18387595
[ "On", "the", "replication", "of", "genetic", "associations:", "timing", "can", "be", "everything!", "The", "failure", "of", "researchers", "to", "replicate", "genetic-association", "findings", "is", "most", "commonly", "attributed", "to", "insufficient", "statistical", "power,", "population", "stratification,", "or", "various", "forms", "of", "between-study", "heterogeneity", "or", "environmental", "influences.(1)", "Here,", "we", "illustrate", "another", "potential", "cause", "for", "nonreplications", "that", "has", "so", "far", "not", "received", "much", "attention", "in", "the", "literature.", "We", "illustrate", "that", "the", "strength", "of", "a", "genetic", "effect", "can", "vary", "by", "age,", "causing", "\"age-varying", "associations.\"", "If", "not", "taken", "into", "account", "during", "the", "design", "and", "the", "analysis", "of", "a", "study,", "age-varying", "genetic", "associations", "can", "cause", "nonreplication.", "By", "using", "the", "100K", "SNP", "scan", "of", "the", "Framingham", "Heart", "Study,", "we", "identified", "an", "age-varying", "association", "between", "a", "SNP", "in", "ROBO1", " ", "and", "obesity", "and", "hypothesized", "an", "age-gene", "interaction.", "This", "finding", "was", "followed", "up", "in", "eight", "independent", "samples", "comprising", "13,584", "individuals.", "The", "association", "was", "replicated", "in", "five", "of", "the", "eight", "studies,", "showing", "an", "age-dependent", "relationship", "(one-sided", "combined", "p", "=", "3.92", "x", "10(-9),", "combined", "p", "value", "from", "pediatric", "cohorts", "=", "2.21", "x", "10(-8),", "combined", "p", "value", "from", "adult", "cohorts", "=", "0.00422).", "Furthermore,", "this", "study", "illustrates", "that", "it", "is", "difficult", "for", "cross-sectional", "study", "designs", "to", "detect", "age-varying", "associations.", "If", "the", "specifics", "of", "age-", "or", "time-varying", "genetic", "effects", "are", "not", "considered", "in", "the", "selection", "of", "both", "the", "follow-up", "samples", "and", "in", "the", "statistical", "analysis,", "important", "genetic", "associations", "may", "be", "missed." ]
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On the replication of genetic associations: timing can be everything! The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.
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12587094
[ "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." ]
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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.
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12325018
[ "rSNP_Guide:", "an", "integrated", "database-tools", "system", "for", "studying", "SNPs", "and", "site-directed", "mutations", "in", "transcription", "factor", "binding", "sites.", "Since", "the", "human", "genome", "was", "sequenced", "in", "draft,", "single", "nucleotide", "polymorphism", "(SNP)", "analysis", "has", "become", "one", "of", "the", "keynote", "fields", "of", "bioinformatics.", "We", "have", "developed", "an", "integrated", "database-tools", "system,", "rSNP_Guide", "(http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/),", "devoted", "to", "prediction", "of", "transcription", "factor", "(TF)", "binding", "sites,", "alterations", "of", "which", "could", "be", "associated", "with", "disease", "phenotype.", "By", "inputting", "data", "on", "alterations", "in", "DNA", "sequence", "and", "in", "DNA", "binding", "pattern", "of", "an", "unknown", "TF,", "rSNP_Guide", "searches", "for", "a", "known", "TF", "with", "alterations", "in", "the", "recognition", "score", "calculated", "on", "the", "basis", "of", "TF", "site's", "sequence", "and", "consistent", "with", "the", "input", "alterations", "in", "DNA", "binding", "to", "the", "unknown", "TF.", "Our", "system", "has", "been", "tested", "on", "many", "relationships", "between", "known", "TF", "sites", "and", "diseases,", "as", "well", "as", "on", "site-directed", "mutagenesis", "data.", "Experimental", "verification", "of", "rSNP_Guide", "system", "was", "made", "on", "functionally", "important", "SNPs", "in", "human", "TDO2and", "mouse", "K-ras", "genes.", "Additional", "examples", "of", "analysis", "are", "reported", "involving", "variants", "in", "the", "human", "gammaA-globin", "(", "HBG1", "),", "hsp70(", "HSPA1A", "),", "and", "Factor", "IX", "(", "F9", "gammaA-globin", " ", "(HBG1),", "hsp70", "(HSPA1A),", "and", "Factor", "IX", "TDO2", "and", "mouse", "K-ras", " ", "genes.", "Additional", "examples", "of", "analysis", "are", "reported", "involving", "variants", "in", "the", "human", "gammaA-globin", "(HBG1),", "hsp70(HSPA1A),", "and", "Factor", "IX", "(F9)", "gene", "promoters." ]
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rSNP_Guide: an integrated database-tools system for studying SNPs and site-directed mutations in transcription factor binding sites. Since the human genome was sequenced in draft, single nucleotide polymorphism (SNP) analysis has become one of the keynote fields of bioinformatics. We have developed an integrated database-tools system, rSNP_Guide (http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/), devoted to prediction of transcription factor (TF) binding sites, alterations of which could be associated with disease phenotype. By inputting data on alterations in DNA sequence and in DNA binding pattern of an unknown TF, rSNP_Guide searches for a known TF with alterations in the recognition score calculated on the basis of TF site's sequence and consistent with the input alterations in DNA binding to the unknown TF. Our system has been tested on many relationships between known TF sites and diseases, as well as on site-directed mutagenesis data. Experimental verification of rSNP_Guide system was made on functionally important SNPs in human TDO2and mouse K-ras genes. Additional examples of analysis are reported involving variants in the human gammaA-globin ( HBG1 ), hsp70( HSPA1A ), and Factor IX ( F9 gammaA-globin (HBG1), hsp70 (HSPA1A), and Factor IX TDO2 and mouse K-ras genes. Additional examples of analysis are reported involving variants in the human gammaA-globin (HBG1), hsp70(HSPA1A), and Factor IX (F9) gene promoters.
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7611293
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A missense mutation ( I278T ) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Cystathionine beta-synthase ( CBS ) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical disease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecular pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C transition in exon 8 causing a substitution of threonine for isoleucine at codon 278 ( I278T ). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation ( G139R and E144K ) in the other allele. The finding that the two patients who are homozygous for I278T I278T threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation (G139R and E144K) in the other allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine responsiveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degree of pyridoxine responsiveness.
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11179004
[ "Connexin", " ", "mutations", "in", "skin", "disease", "and", "hearing", "loss." ]
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Connexin mutations in skin disease and hearing loss.
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9399882
[ "Inherited", "interstitial", "duplications", "of", "proximal", "15q:", "genotype-phenotype", "correlations.", "We", "present", "the", "cytogenetic,", "molecular", "cytogenetic,", "and", "molecular", "genetic", "results", "on", "20", "unrelated", "patients", "with", "an", "interstitial", "duplication", "of", "the", "proximal", "long", "arm", "of", "chromosome", "15.", "Multiple", "probes", "showed", "that", "the", "Prader-Willi/Angelman", "critical", "region", "(PWACR)", "was", "included", "in", "the", "duplication", "in", "4/20", "patients,", "each", "ascertained", "with", "developmental", "delay.", "The", "duplication", "was", "also", "found", "in", "two", "affected", "but", "not", "in", "three", "unaffected", "sibs", "of", "one", "of", "these", "patients.", "All", "four", "probands", "had", "inherited", "their", "duplication", "from", "their", "mothers,", "three", "of", "whom", "were", "also", "affected.", "Two", "of", "the", "affected", "mothers", "also", "carried", "a", "maternally", "inherited", "duplication,", "whereas", "the", "duplication", "in", "the", "unaffected", "mother", "and", "in", "an", "unaffected", "grandmother", "was", "paternal", "in", "origin,", "raising", "the", "possibility", "of", "a", "parental-origin", "effect.", "The", "PWACR", "was", "not", "duplicated", "in", "the", "remaining", "16", "patients,", "of", "whom", "4", "were", "referred", "with", "developmental", "delay.", "In", "the", "14", "families", "for", "which", "parental", "samples", "were", "available,", "the", "duplication", "was", "inherited", "with", "equal", "frequency", "from", "a", "phenotypically", "normal", "parent,", "mother", "or", "father.", "Comparative", "genomic", "hybridization", "undertaken", "on", "two", "patients", "suggested", "that", "proximal", "15q", "outside", "the", "PWACR", "was", "the", "origin", "of", "the", "duplicated", "material.", "The", "use", "of", "PWACR", "probes", "discriminates", "between", "a", "large", "group", "of", "duplications", "of", "no", "apparent", "clinical", "significance", "and", "a", "smaller", "group,", "in", "which", "a", "maternally", "derived", "PWACR", "duplication", "is", "consistently", "associated", "with", "developmental", "delay", "and", "speech", "difficulties", "but", "not", "with", "overt", "features", "of", "either", "Prader-Willi", "syndrome", "or", "Angelman", "syndrome." ]
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Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations. We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.
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Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions. Serial replication slippage in cis (SRScis) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra- and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRStrans) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of >or=5 bp but <1 kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRStrans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. The remaining lesion, a 31-kb segmental duplication associated with a small inversion in the SLC3A1 gene, is explicable in terms of a modified SRS model that integrates the concept of "break-induced replication." This study therefore lends broad support to our postulate that intrachromosomal SRStrans can account for a variety of complex gene rearrangements that involve inversions.
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10533067
[ "Analysis", "of", "both", "TSC1", " ", "and", "TSC2", " ", "for", "germline", "mutations", "in", "126", "unrelated", "patients", "with", "tuberous", "sclerosis.", "Tuberous", "sclerosis", "complex", "(TSC)", "is", "an", "autosomal", "dominant", "disorder", "characterized", "by", "the", "development", "of", "multiple", "hamartomas", "involving", "many", "organs.", "About", "two-thirds", "of", "the", "cases", "are", "sporadic", "and", "appear", "to", "represent", "new", "mutations.", "With", "the", "cloning", "of", "two", "causative", "genes,", "TSC1", " ", "and", "TSC2", " ", "it", "is", "now", "possible", "to", "analyze", "both", "genes", "in", "TSC", "patients", "and", "identify", "germline", "mutations.", "Here", "we", "report", "the", "mutational", "analysis", "of", "the", "entire", "coding", "region", "of", "both", "TSC1", " ", "and", "TSC2", " ", "genes", "in", "126", "unrelated", "TSC", "patients,", "including", "40", "familial", "and", "86", "sporadic", "cases,", "by", "single-stranded", "conformational", "polymorphism", "(SSCP)", "analysis", "followed", "by", "direct", "sequencing.", "Mutations", "were", "identified", "in", "a", "total", "of", "74", "(59%)", "cases,", "including", "16", "TSC1", " ", "mutations", "(5", "sporadic", "and", "11", "familial", "cases)", "and", "58", "TSC2", " ", "mutations", "(42", "sporadic", "and", "16", "familial", "cases).", "Overall,", "significantly", "more", "TSC2", " ", "mutations", "were", "found", "in", "our", "population,", "with", "a", "relatively", "equal", "distribution", "of", "mutations", "between", "TSC1", " ", "and", "TSC2", " ", "among", "the", "familial", "cases,", "but", "a", "marked", "underrepresentation", "of", "TSC1", " ", "mutations", "among", "the", "sporadic", "cases", "(P", "=", "0.0035,", "Fisher's", "exact", "test).", "All", "TSC1", " ", "mutations", "were", "predicted", "to", "be", "protein", "truncating.", "However,", "in", "TSC2", " ", "13", "missense", "mutations", "were", "found,", "five", "clustering", "in", "the", "GAP-related", "domain", "and", "three", "others", "occurring", "in", "exon", "16.", "Upon", "comparison", "of", "clinical", "manifestations,", "including", "the", "incidence", "of", "intellectual", "disability,", "we", "could", "not", "find", "any", "observable", "differences", "between", "TSC1", " ", "and", "TSC2", " ", "patients.", "Our", "data", "help", "define", "the", "distribution", "and", "spectrum", "of", "mutations", "associated", "with", "the", "TSC", " ", "loci", "and", "will", "be", "useful", "for", "both", "understanding", "the", "function", "of", "these", "genes", "as", "well", "as", "genetic", "counseling", "in", "patients", "with", "the", "disease." ]
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Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of multiple hamartomas involving many organs. About two-thirds of the cases are sporadic and appear to represent new mutations. With the cloning of two causative genes, TSC1 and TSC2 it is now possible to analyze both genes in TSC patients and identify germline mutations. Here we report the mutational analysis of the entire coding region of both TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by single-stranded conformational polymorphism (SSCP) analysis followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial cases) and 58 TSC2 mutations (42 sporadic and 16 familial cases). Overall, significantly more TSC2 mutations were found in our population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (P = 0.0035, Fisher's exact test). All TSC1 mutations were predicted to be protein truncating. However, in TSC2 13 missense mutations were found, five clustering in the GAP-related domain and three others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, we could not find any observable differences between TSC1 and TSC2 patients. Our data help define the distribution and spectrum of mutations associated with the TSC loci and will be useful for both understanding the function of these genes as well as genetic counseling in patients with the disease.
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17203459
[ "ZFHX1B", " ", "mutations", "in", "patients", "with", "Mowat-Wilson", "syndrome.", "Mowat-Wilson", "syndrome", "(MWS)", "is", "a", "recently", "delineated", "mental", "retardation", "(MR)-multiple", "congenital", "anomaly", "syndrome,", "characterized", "by", "typical", "facies,", "severe", "MR,", "epilepsy,", "and", "variable", "congenital", "malformations,", "including", "Hirschsprung", "disease", "(HSCR),", "genital", "anomalies,", "congenital", "heart", "disease", "(CHD),", "and", "agenesis", "of", "the", "corpus", "callosum", "(ACC).", "It", "is", "caused", "by", "de", "novo", "heterozygous", "mutations", "or", "deletions", "of", "the", "ZFHX1B", " ", "gene", "located", "at", "2q22.", "ZFHX1B", " ", "encodes", "Smad-interacting", "protein-1", " ", "(", "SMADIP1", " ", "or", "SIP1", "),", "a", "transcriptional", "corepressor", "involved", "in", "the", "transforming", "growth", "factor-beta", "signaling", "pathway.", "It", "is", "a", "highly", "evolutionarily", "conserved", "gene,", "widely", "expressed", "in", "embryological", "development.", "Over", "100", "mutations", "have", "been", "described", "in", "patients", "with", "clinically", "typical", "MWS,", "who", "almost", "always", "have", "whole", "gene", "deletions", "or", "truncating", "mutations", "(nonsense", "or", "frameshift)", "of", "ZFHX1B", ",", "suggesting", "that", "haploinsufficiency", "is", "the", "basis", "of", "MWS", "pathology.", "No", "obvious", "genotype-phenotype", "correlation", "could", "be", "identified", "so", "far,", "but", "atypical", "phenotypes", "have", "been", "reported", "with", "missense", "or", "splice", "mutations", "in", "the", "ZFHX1B", " ", "gene.", "In", "this", "work", "we", "describe", "40", "novel", "mutations", "and", "we", "summarize", "the", "various", "mutational", "reports", "published", "since", "the", "identification", "of", "the", "causative", "gene." ]
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ZFHX1B mutations in patients with Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). It is caused by de novo heterozygous mutations or deletions of the ZFHX1B gene located at 2q22. ZFHX1B encodes Smad-interacting protein-1 ( SMADIP1 or SIP1 ), a transcriptional corepressor involved in the transforming growth factor-beta signaling pathway. It is a highly evolutionarily conserved gene, widely expressed in embryological development. Over 100 mutations have been described in patients with clinically typical MWS, who almost always have whole gene deletions or truncating mutations (nonsense or frameshift) of ZFHX1B , suggesting that haploinsufficiency is the basis of MWS pathology. No obvious genotype-phenotype correlation could be identified so far, but atypical phenotypes have been reported with missense or splice mutations in the ZFHX1B gene. In this work we describe 40 novel mutations and we summarize the various mutational reports published since the identification of the causative gene.
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11822023
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Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin. During human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual gamma-globin expression being restricted to a subset of erythrocytes termed "F cells" (FC). Statistical analyses have shown the FC trait to be influenced by a common sequence variant (C-->T) at position -158 upstream of the Ggamma-globin (C-->T) at position -158 upstream of the Ggamma-globin gene, termed the "XmnI-Ggamma polymorphism." The XmnI-Ggamma site is believed to be involved in the expression of the Ggamma-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Ggamma site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Ggamma site, we showed suggestive linkage to chromosome 8q. A maximum single-point LOD score of 4.33 and a multipoint LOD score of 4.75 were found in a 15-20 cM region of chromosome 8q. A single-locus analysis failed to show linkage of FC to the region when the XmnI-Ggamma site was accounted for by removing its effects from the data or including it as a covariate. Results of the single-locus analysis were significant when the effects of the XmnI-Ggamma site were not accounted for in any way. The results of analysis in a large Indian kindred indicate that there is an interaction between the XmnI-Ggamma site and a QTL on chromosome 8q that is influencing the production of fetal Hb.
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16642433
[ "Polymorphism", "in", "maternal", "LRP8", " ", "gene", "is", "associated", "with", "fetal", "growth.", "Fetal", "growth", "restriction", "(FGR)", "affects", ">200,000", "pregnancies", "in", "the", "United", "States", "annually", "and", "is", "associated", "with", "increased", "perinatal", "mortality", "and", "morbidity,", "as", "well", "as", "poorer", "long-term", "health", "for", "infants", "with", "FGR", "compared", "with", "infants", "without", "FGR.", "FGR", "appears", "to", "be", "a", "complex", "trait,", "but", "the", "role", "of", "genetic", "factors", "in", "the", "development", "of", "FGR", "is", "largely", "unknown.", "We", "conducted", "a", "candidate-gene", "association", "study", "of", "birth", "weight", "and", "FGR", "in", "two", "independent", "study", "samples", "obtained", "at", "the", "Boston", "Medical", "Center.", "We", "first", "investigated", "the", "association", "between", "maternal", "genotypes", "of", "68", "single-nucleotide", "polymorphisms", "(SNPs)", "from", "41", "candidate", "genes", "and", "fetal", "growth", "in", "a", "sample", "of", "204", "black", "women", "selected", "for", "a", "previous", "study", "of", "preeclampsia,", "92", "of", "whom", "had", "preeclampsia", "(characterized", "by", "high", "blood", "pressure", "and", "the", "presence", "of", "protein", "in", "the", "urine).", "We", "found", "significant", "association", "between", "SNP", "rs2297660", "in", "the", "LRP8", " ", "gene", "and", "birth", "weight.", "Subsequently,", "we", "replicated", "the", "association", "in", "a", "larger", "independent", "sample", "of", "1,094", "black", "women;", "similar", "association", "between", "LRP8", " ", "and", "FGR", "was", "observed", "in", "this", "sample.", "The", "\"A\"", "allele", "at", "rs2297660", "was", "associated", "with", "a", "higher", "standardized", "birth", "weight", "and", "a", "lower", "risk", "of", "FGR.", "Under", "the", "additive", "genetic", "model,", "each", "additional", "copy", "of", "the", "\"A\"", "allele", "reduced", "the", "risk", "of", "FGR", "by", "33%", "(P<.05).", "In", "conclusion,", "results", "from", "the", "two", "independent", "samples", "of", "black", "women", "provide", "consistent", "evidence", "that", "SNP", "rs2297660", "in", "LRP8", " ", "is", "associated", "with", "fetal", "growth." ]
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Polymorphism in maternal LRP8 gene is associated with fetal growth. Fetal growth restriction (FGR) affects >200,000 pregnancies in the United States annually and is associated with increased perinatal mortality and morbidity, as well as poorer long-term health for infants with FGR compared with infants without FGR. FGR appears to be a complex trait, but the role of genetic factors in the development of FGR is largely unknown. We conducted a candidate-gene association study of birth weight and FGR in two independent study samples obtained at the Boston Medical Center. We first investigated the association between maternal genotypes of 68 single-nucleotide polymorphisms (SNPs) from 41 candidate genes and fetal growth in a sample of 204 black women selected for a previous study of preeclampsia, 92 of whom had preeclampsia (characterized by high blood pressure and the presence of protein in the urine). We found significant association between SNP rs2297660 in the LRP8 gene and birth weight. Subsequently, we replicated the association in a larger independent sample of 1,094 black women; similar association between LRP8 and FGR was observed in this sample. The "A" allele at rs2297660 was associated with a higher standardized birth weight and a lower risk of FGR. Under the additive genetic model, each additional copy of the "A" allele reduced the risk of FGR by 33% (P<.05). In conclusion, results from the two independent samples of black women provide consistent evidence that SNP rs2297660 in LRP8 is associated with fetal growth.
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8116617
[ "Paternal", "isodisomy", "for", "chromosome", "5", "in", "a", "child", "with", "spinal", "muscular", "atrophy.", "Paternal", "isodisomy", "for", "chromosome", "5", "was", "detected", "in", "a", "2-year-old", "boy", "with", "type", "III", "spinal", "muscular", "atrophy", "(SMA),", "an", "autosomal", "recessive", "degenerative", "disorder", "of", "alpha", "motor", "neurons,", "known", "to", "map", "to", "5q11.2-13.3.", "Examination", "of", "17", "short-sequence", "repeat", "polymorphisms", "spanning", "5p15.1-15.3", "to", "5q33.3-qter", "produced", "no", "evidence", "of", "maternally", "inherited", "alleles.", "Cytogenetic", "analysis", "revealed", "a", "normal", "male", "karyotype,", "and", "FISH", "with", "probes", "closely", "flanking", "the", "SMA", "locus", "confirmed", "the", "presence", "of", "two", "copies", "of", "chromosome", "5.", "No", "developmental", "abnormalities,", "other", "than", "those", "attributable", "to", "classical", "childhood-onset", "SMA,", "were", "present.", "While", "the", "absence", "of", "a", "maternally", "derived", "chromosome", "5", "could", "have", "produced", "the", "symptoms", "of", "SMA", "through", "the", "mechanisms", "of", "genomic", "imprinting,", "the", "lack", "of", "more", "global", "developmental", "abnormalities", "would", "be", "unusual.", "Paternal", "transmission", "of", "two", "copies", "of", "a", "defective", "gene", "at", "the", "SMA", "locus", "seems", "to", "be", "the", "most", "likely", "cause", "of", "disease,", "but", "proof", "of", "this", "will", "have", "to", "await", "the", "identification", "of", "the", "SMA", " ", "gene.", "While", "uniparental", "isodisomy", "is", "a", "rare", "event,", "it", "must", "be", "considered", "as", "a", "possible", "mechanism", "involved", "in", "SMA", "SMA", "SMA", "SMA,", "SMA", "SMA", "),", "an", "autosomal", "recessive", "degenerative", "disorder", "of", "alpha", "motor", "neurons,", "known", "to", "map", "to", "5q11.2-13.3.", "Examination", "of", "17", "short-sequence", "repeat", "polymorphisms", "spanning", "5p15.1-15.3", "to", "5q33.3-qter", "produced", "no", "evidence", "of", "maternally", "inherited", "alleles.", "Cytogenetic", "analysis", "revealed", "a", "normal", "male", "karyotype,", "and", "FISH", "with", "probes", "closely", "flanking", "the", "SMA", "locus", "confirmed", "the", "presence", "of", "two", "copies", "of", "chromosome", "5.", "No", "developmental", "abnormalities,", "other", "than", "those", "attributable", "to", "classical", "childhood-onset", "SMA,", "were", "present.", "While", "the", "absence", "of", "a", "maternally", "derived", "chromosome", "5", "could", "have", "produced", "the", "symptoms", "of", "SMA", "through", "the", "mechanisms", "of", "genomic", "imprinting,", "the", "lack", "of", "more", "global", "developmental", "abnormalities", "would", "be", "unusual.", "Paternal", "transmission", "of", "two", "copies", "of", "a", "defective", "gene", "at", "the", "SMA", "locus", "seems", "to", "be", "the", "most", "likely", "cause", "of", "disease,", "but", "proof", "of", "this", "will", "have", "to", "await", "the", "identification", "of", "the", "SMA", "gene.", "While", "uniparental", "isodisomy", "is", "a", "rare", "event,", "it", "must", "be", "considered", "as", "a", "possible", "mechanism", "involved", "in", "SMA", "when", "conducting", "prenatal", "testing", "and", "counseling", "for", "this", "disorder." ]
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Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy. Paternal isodisomy for chromosome 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3 to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanisms of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA SMA SMA SMA, SMA SMA ), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3 to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanisms of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder.
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17436254
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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.
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19118813
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Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 ( NRG3 ). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1 , a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.
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10417286
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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.
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12655559
[ "Gene", "structure", "of", "human", "carbamylphosphate", "synthetase", "1", "and", "novel", "mutations", "in", "patients", "with", "neonatal", "onset.", "Carbamylphosphate", "synthetase", "1", "(E.C.", "6.3.4.16)", "deficiency", "is", "a", "rare", "autosomal", "recessive", "disorder", "of", "the", "urea", "cycle", "that", "can", "result", "in", "severe", "neonatal", "hyperammonemia.", "Since", "the", "genomic", "structure", "of", "the", "CPS1", " ", "gene", "was", "not", "yet", "elucidated,", "mutation", "detection", "was", "performed", "by", "analysis", "of", "transcripts", "in", "the", "past.", "Here,", "we", "present", "the", "entire", "DNA", "sequence", "of", "the", "human", "CPS1", " ", "gene", "including", "all", "exon-intron", "boundaries.", "Moreover,", "mutation", "analysis", "was", "performed", "in", "six", "patients", "leading", "to", "the", "detection", "of", "9", "novel", "mutations", "including", "the", "missense", "mutations", "c.2528T>C", " ", "and", "c.2623A>G", ",", "the", "nonsense", "mutations", "c.712C>T", " ", "and", "c.2115ins35bp", ",", "the", "splice", "site", "mutations", "c.1263+5G>C", ",", "c.3558+1G>C", " ", "and", "c.4101+2T>C", ",", "and", "a", "small", "deletion", "c.3036_3038delGGT", ".", "The", "mutations", "c.2528T>C", " ", "and", "c.2623A>G", " ", "were", "identified", "on", "a", "double", "mutated", "allele.", "New", "data", "on", "the", "genomic", "structure", "of", "the", "CPS1", " ", "gene", "provided", "in", "this", "study", "are", "useful", "to", "characterize", "the", "heterogenous", "molecular", "basis", "of", "the", "disease", "in", "patients", "deficient", "for", "carbamylphosphate", "1", "deficiency." ]
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Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Carbamylphosphate synthetase 1 (E.C. 6.3.4.16) deficiency is a rare autosomal recessive disorder of the urea cycle that can result in severe neonatal hyperammonemia. Since the genomic structure of the CPS1 gene was not yet elucidated, mutation detection was performed by analysis of transcripts in the past. Here, we present the entire DNA sequence of the human CPS1 gene including all exon-intron boundaries. Moreover, mutation analysis was performed in six patients leading to the detection of 9 novel mutations including the missense mutations c.2528T>C and c.2623A>G , the nonsense mutations c.712C>T and c.2115ins35bp , the splice site mutations c.1263+5G>C , c.3558+1G>C and c.4101+2T>C , and a small deletion c.3036_3038delGGT . The mutations c.2528T>C and c.2623A>G were identified on a double mutated allele. New data on the genomic structure of the CPS1 gene provided in this study are useful to characterize the heterogenous molecular basis of the disease in patients deficient for carbamylphosphate 1 deficiency.
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19732864
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Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type 1 diabetes, primary biliary cirrhosis, and Crohn disease. Previous reports by us and others have linked the disease-associated genetic variants with changes in expression of GSDMB and ORMDL3 transcripts in human lymphoblastoid cell lines (LCLs). The variants also alter regulation of other transcripts, and this domain-wide cis-regulatory effect suggests a mechanism involving long-range chromatin interactions. Here, we further dissect the disease-linked haplotype and identify putative causal DNA variants via a combination of genetic and functional analyses. First, high-throughput resequencing of the region and genotyping of potential candidate variants were performed. Next, additional mapping of allelic expression differences in Yoruba HapMap LCLs allowed us to fine-map the basis of the cis-regulatory differences to a handful of candidate functional variants. Functional assays identified allele-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF , as well as a weak promoter activity for rs12936231. Overall, this study shows a common disease allele linked to changes in CTCF ZPBP2 / GSDMB / ORMDL3 locus associated with the risk of asthma and autoimmune disease. Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type 1 diabetes, primary biliary cirrhosis, and Crohn disease. Previous reports by us and others have linked the disease-associated genetic variants with changes in expression of GSDMB and ORMDL3 transcripts in human lymphoblastoid cell lines (LCLs). The variants also alter regulation of other transcripts, and this domain-wide cis-regulatory effect suggests a mechanism involving long-range chromatin interactions. Here, we further dissect the disease-linked haplotype and identify putative causal DNA variants via a combination of genetic and functional analyses. First, high-throughput resequencing of the region and genotyping of potential candidate variants were performed. Next, additional mapping of allelic expression differences in Yoruba HapMap LCLs allowed us to fine-map the basis of the cis-regulatory differences to a handful of candidate functional variants. Functional assays identified allele-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF, as well as a weak promoter activity for rs12936231. Overall, this study shows a common disease allele linked to changes in CTCF binding and nucleosome occupancy leading to altered domain-wide cis-regulation. Finally, a strong association between asthma and cis-regulatory haplotypes was observed in three independent family-based cohorts (p = 1.78 x 10(-8)). This study demonstrates the requirement of multiple parallel allele-specific tools for the investigation of noncoding disease variants and functional fine-mapping of human disease-associated haplotypes.
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20579627
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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 p. W177R ]) in exon 3 of both the long-wavelength-sensitive ( LW 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).
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12497643
[ "Splice", "mutations", "in", "the", "p53", " ", "gene:", "case", "report", "and", "review", "of", "the", "literature.", "Splice", "mutations", "in", "the", "p53", " ", "gene", "(", "TP53", ")", "are", "described", "as", "rare", "events", "that", "occur", "at", "a", "frequency", "of", "less", "than", "1%.", "Using", "a", "functional", "assay", "based", "on", "the", "transcriptional", "activity", "of", "p53", " ", "and", "using", "RNA", "as", "starting", "material,", "we", "describe", "here", "a", "p53", " ", "splice", "mutation", "that", "could", "not", "be", "detected", "by", "genomic", "sequencing.", "This", "lack", "of", "detection", "is", "due", "to", "a", "deletion", "of", "the", "region", "complementary", "to", "primers", "commonly", "used", "for", "amplification.", "Reviewing", "the", "literature,", "we", "show", "that", "p53", " ", "splice", "mutations", "have", "been", "certainly", "underestimated", "and", "that", "careful", "strategy", "should", "be", "used", "for", "a", "complete", "mutational", "analysis", "of", "the", "p53", " ", "gene.", "Furthermore,", "some", "p53", " ", "gene", "mutations", "described", "as", "\"neutral\"", "due", "to", "the", "absence", "of", "any", "amino-acid", "change", "are", "truly", "deleterious,", "as", "they", "affect", "gene", "splicing." ]
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Splice mutations in the p53 gene: case report and review of the literature. Splice mutations in the p53 gene ( TP53 ) are described as rare events that occur at a frequency of less than 1%. Using a functional assay based on the transcriptional activity of p53 and using RNA as starting material, we describe here a p53 splice mutation that could not be detected by genomic sequencing. This lack of detection is due to a deletion of the region complementary to primers commonly used for amplification. Reviewing the literature, we show that p53 splice mutations have been certainly underestimated and that careful strategy should be used for a complete mutational analysis of the p53 gene. Furthermore, some p53 gene mutations described as "neutral" due to the absence of any amino-acid change are truly deleterious, as they affect gene splicing.
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17594715
[ "Spectrum", "of", "ALMS1", " ", "variants", "and", "evaluation", "of", "genotype-phenotype", "correlations", "in", "Alström", "syndrome.", "Alström", "syndrome", "is", "a", "monogenic", "recessive", "disorder", "featuring", "an", "array", "of", "clinical", "manifestations,", "with", "systemic", "fibrosis", "and", "multiple", "organ", "involvement,", "including", "retinal", "degeneration,", "hearing", "loss,", "childhood", "obesity,", "diabetes", "mellitus,", "dilated", "cardiomyopathy", "(DCM),", "urological", "dysfunction,", "and", "pulmonary,", "hepatic,", "and", "renal", "failure.", "We", "evaluated", "a", "large", "cohort", "of", "patients", "with", "Alström", "syndrome", "for", "mutations", "in", "the", "ALMS1", " ", "gene.", "In", "total,", "79", "disease-causing", "variants", "were", "identified,", "of", "which", "55", "are", "novel", "mutations.", "The", "variants", "are", "primarily", "clustered", "in", "exons", "8,", "10,", "and", "16,", "although", "we", "also", "identified", "novel", "mutations", "in", "exons", "12", "and", "18.", "Most", "alleles", "were", "identified", "only", "once", "(45/79),", "but", "several", "were", "found", "recurrently.", "Founder", "effects", "are", "likely", "in", "families", "of", "English", "and", "Turkish", "descent.", "We", "also", "identified", "66", "SNPs", "and", "assessed", "the", "functional", "significance", "of", "these", "variants", "based", "on", "the", "conserved", "identity", "of", "the", "protein", "and", "the", "severity", "of", "the", "resulting", "amino", "acid", "substitution.", "A", "genotype-phenotype", "association", "study", "examining", "18", "phenotypic", "parameters", "in", "a", "subset", "of", "58", "patients", "found", "suggestive", "associations", "between", "disease-causing", "variants", "in", "exon", "16", "and", "the", "onset", "of", "retinal", "degeneration", "before", "the", "age", "of", "1", "year", "(P", "=", "0.02),", "the", "occurrence", "of", "urological", "dysfunction", "(P", "=", "0.02),", "of", "DCM", "(P", "=", "0.03),", "and", "of", "diabetes", "(P", "=", "0.03).", "A", "significant", "association", "was", "found", "between", "alterations", "in", "exon", "8", "and", "absent,", "mild,", "or", "delayed", "renal", "disease", "(P", "=", "0.0007).", "This", "data", "may", "have", "implications", "for", "the", "understanding", "of", "the", "molecular", "mechanisms", "of", "ALMS1", "and", "provides", "the", "basis", "for", "further", "investigation", "of", "how", "alternative", "splicing", "of", "ALMS1", " ", "contributes", "to", "the", "severity", "of", "the", "disease." ]
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Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Alström syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alström syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease.
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9633815
[ "Spectrum", "of", "mutations", "in", "the", "fumarylacetoacetate", "hydrolase", " ", "gene", "of", "tyrosinemia", "type", "1", "patients", "in", "northwestern", "Europe", "and", "Mediterranean", "countries.", "Hereditary", "tyrosinemia", "type", "1", "(HT1)", "is", "a", "rare", "metabolic", "disease", "caused", "by", "a", "deficient", "activity", "of", "the", "enzyme", "fumarylacetoacetase", "(FAH).", "To", "investigate", "the", "molecular", "heterogeneity", "of", "tyrosinemia,", "the", "geographic", "distribution", "and", "the", "genotype-phenotype", "relationship,", "we", "have", "analyzed", "the", "FAH", "genotype", "of", "25", "HT1", "patients.", "Mutation", "screening", "was", "performed", "by", "PCR", "amplification", "of", "exons", "1-14", "of", "the", "FAH", "gene,", "followed", "by", "SSCP", "analysis", "and", "direct", "sequencing", "of", "the", "amplified", "exons.", "Fourteen", "different", "mutations", "were", "found,", "of", "which", "seven", "were", "novel,", "viz.", "three", "missense", "mutations", "(", "G158D", ",", "P261L", ",", "F405H", "FAH", " ", "gene,", "followed", "by", "SSCP", "analysis", "and", "direct", "sequencing", "of", "the", "amplified", "exons.", "Fourteen", "different", "mutations", "were", "found,", "of", "which", "seven", "were", "novel,", "viz.", "three", "missense", "mutations", "(G158D,", "P261L,", "F405H),", "a", "deletion", "of", "three", "nucleotides", "causing", "a", "deletion", "of", "serine", "(", "DEL366S", ")", "and", "three", "splice", "site", "mutations:", "IVS2+1(g-t)", ",", "IVS6-1(g-c)", ",", "IVS8-1(g-c)", ".", "The", "splice", "site", "mutations", "IVS6-1(g-t)", " ", "and", "IVS12+5(g-a)", " ", "were", "frequently", "found", "in", "countries", "around", "the", "Mediterranean", "and", "northwestern", "Europe,", "respectively.", "No", "clear", "correlation", "between", "the", "genotype", "and", "the", "three", "major", "HT1", "subtypes", "could", "be", "established." ]
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Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries. Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a deficient activity of the enzyme fumarylacetoacetase (FAH). To investigate the molecular heterogeneity of tyrosinemia, the geographic distribution and the genotype-phenotype relationship, we have analyzed the FAH genotype of 25 HT1 patients. Mutation screening was performed by PCR amplification of exons 1-14 of the FAH gene, followed by SSCP analysis and direct sequencing of the amplified exons. Fourteen different mutations were found, of which seven were novel, viz. three missense mutations ( G158D , P261L , F405H FAH gene, followed by SSCP analysis and direct sequencing of the amplified exons. Fourteen different mutations were found, of which seven were novel, viz. three missense mutations (G158D, P261L, F405H), a deletion of three nucleotides causing a deletion of serine ( DEL366S ) and three splice site mutations: IVS2+1(g-t) , IVS6-1(g-c) , IVS8-1(g-c) . The splice site mutations IVS6-1(g-t) and IVS12+5(g-a) were frequently found in countries around the Mediterranean and northwestern Europe, respectively. No clear correlation between the genotype and the three major HT1 subtypes could be established.
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9042937
[ "HLA", "sharing", "and", "history", "of", "miscarriage", "among", "women", "with", "rheumatoid", "arthritis." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
HLA sharing and history of miscarriage among women with rheumatoid arthritis.
[ 2, 7225, 10763, 1930, 4403, 1927, 29670, 2706, 3089, 1956, 13053, 8884, 18, 3 ]
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8434605
[ "Identification", "of", "individuals", "by", "analysis", "of", "biallelic", "DNA", "markers,", "using", "PCR", "and", "solid-phase", "minisequencing.", "We", "have", "developed", "a", "new", "method", "for", "forensic", "identification", "of", "individuals,", "in", "which", "a", "panel", "of", "biallelic", "DNA", "markers", "are", "amplified", "by", "the", "PCR,", "and", "the", "variable", "nucleotides", "are", "detected", "in", "the", "amplified", "DNA", "fragments", "by", "the", "solid-phase", "minisequencing", "method.", "A", "panel", "of", "12", "common", "polymorphic", "nucleotides", "located", "on", "different", "chromosomes", "with", "reported", "allele", "frequencies", "close", "to", ".5", "were", "chosen", "for", "the", "test.", "The", "allele", "frequencies", "for", "most", "of", "the", "markers", "were", "found", "to", "be", "similar", "in", "the", "Finnish", "and", "other", "Caucasian", "populations.", "We", "also", "introduce", "a", "novel", "approach", "for", "rapid", "determination", "of", "the", "population", "frequencies", "of", "biallelic", "markers.", "By", "this", "approach", "we", "were", "able", "to", "determine", "the", "allele", "frequencies", "of", "the", "markers", "in", "the", "Finnish", "population,", "by", "quantitative", "analysis", "of", "three", "pooled", "DNA", "samples", "representing", "3,000", "individuals.", "The", "power", "of", "discrimination", "and", "exclusion", "of", "the", "solid-phase", "minisequencing", "typing", "test", "with", "12", "markers", "was", "similar", "to", "that", "of", "three", "VNTR", "markers", "that", "are", "routinely", "used", "in", "forensic", "analyses", "at", "our", "institute.", "The", "solid-phase", "minisequencing", "method", "was", "successfully", "applied", "to", "type", "paternity", "and", "forensic", "case", "samples.", "We", "also", "show", "that", "the", "quantitative", "nature", "of", "our", "method", "allows", "typing", "of", "mixed", "samples." ]
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Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing. We have developed a new method for forensic identification of individuals, in which a panel of biallelic DNA markers are amplified by the PCR, and the variable nucleotides are detected in the amplified DNA fragments by the solid-phase minisequencing method. A panel of 12 common polymorphic nucleotides located on different chromosomes with reported allele frequencies close to .5 were chosen for the test. The allele frequencies for most of the markers were found to be similar in the Finnish and other Caucasian populations. We also introduce a novel approach for rapid determination of the population frequencies of biallelic markers. By this approach we were able to determine the allele frequencies of the markers in the Finnish population, by quantitative analysis of three pooled DNA samples representing 3,000 individuals. The power of discrimination and exclusion of the solid-phase minisequencing typing test with 12 markers was similar to that of three VNTR markers that are routinely used in forensic analyses at our institute. The solid-phase minisequencing method was successfully applied to type paternity and forensic case samples. We also show that the quantitative nature of our method allows typing of mixed samples.
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16642442
[ "Breakpoint", "cloning", "and", "haplotype", "analysis", "indicate", "a", "single", "origin", "of", "the", "common", "Inv(10)(p11.2q21.2)", "mutation", "among", "northern", "Europeans.", "The", "pericentric", "inv(10)(p11.2q21.2)", "mutation", "has", "been", "frequently", "identified", "in", "cytogenetic", "laboratories,", "is", "phenotypically", "silent,", "and", "is", "considered", "to", "be", "a", "polymorphic", "variant.", "Cloning", "and", "sequencing", "of", "the", "junction", "fragments", "on", "10p11", "and", "10q21", "revealed", "that", "neither", "inversion", "breakpoint", "directly", "involved", "any", "genes", "or", "repetitive", "sequences,", "although", "both", "breakpoint", "regions", "contain", "a", "number", "of", "repeats.", "All", "20", "apparently", "unrelated", "inv(10)", "families", "in", "our", "study", "had", "identical", "breakpoints,", "and", "detailed", "haplotype", "analysis", "showed", "that", "the", "inversions", "were", "identical", "by", "descent.", "Thus,", "although", "considered", "a", "common", "variant,", "inv(10)(p11.2q21.2)", "has", "a", "single", "ancestral", "founder", "among", "northern", "Europeans." ]
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Breakpoint cloning and haplotype analysis indicate a single origin of the common Inv(10)(p11.2q21.2) mutation among northern Europeans. The pericentric inv(10)(p11.2q21.2) mutation has been frequently identified in cytogenetic laboratories, is phenotypically silent, and is considered to be a polymorphic variant. Cloning and sequencing of the junction fragments on 10p11 and 10q21 revealed that neither inversion breakpoint directly involved any genes or repetitive sequences, although both breakpoint regions contain a number of repeats. All 20 apparently unrelated inv(10) families in our study had identical breakpoints, and detailed haplotype analysis showed that the inversions were identical by descent. Thus, although considered a common variant, inv(10)(p11.2q21.2) has a single ancestral founder among northern Europeans.
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11083947
[ "Extent", "and", "distribution", "of", "linkage", "disequilibrium", "in", "three", "genomic", "regions.", "The", "positional", "cloning", "of", "genes", "underlying", "common", "complex", "diseases", "relies", "on", "the", "identification", "of", "linkage", "disequilibrium", "(LD)", "between", "genetic", "markers", "and", "disease.", "We", "have", "examined", "127", "polymorphisms", "in", "three", "genomic", "regions", "in", "a", "sample", "of", "575", "chromosomes", "from", "unrelated", "individuals", "of", "British", "ancestry.", "To", "establish", "phase,", "800", "individuals", "were", "genotyped", "in", "160", "families.", "The", "fine", "structure", "of", "LD", "was", "found", "to", "be", "highly", "irregular.", "Forty-five", "percent", "of", "the", "variation", "in", "disequilibrium", "measures", "could", "be", "explained", "by", "physical", "distance.", "Additional", "factors,", "such", "as", "allele", "frequency,", "type", "of", "polymorphism,", "and", "genomic", "location,", "explained", "<5%", "of", "the", "variation.", "Nevertheless,", "disequilibrium", "was", "occasionally", "detectable", "at", "500", "kb", "and", "was", "present", "for", "over", "one-half", "of", "marker", "pairs", "separated", "by", "<50", "kb.", "Although", "these", "findings", "are", "encouraging", "for", "the", "prospects", "of", "a", "genomewide", "LD", "map,", "they", "suggest", "caution", "in", "interpreting", "localization", "due", "to", "allelic", "association." ]
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Extent and distribution of linkage disequilibrium in three genomic regions. The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.
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8198127
[ "The", "genetic", "locus", "for", "free", "sialic", "acid", "storage", "disease", "maps", "to", "the", "long", "arm", "of", "chromosome", "6.", "Salla", "disease", "(SD),", "or", "adult-type", "free", "sialic", "acid", "storage", "disease,", "is", "an", "autosomal", "recessive", "lysosomal", "storage", "disorder", "characterized", "by", "impaired", "transport", "of", "free", "sialic", "acid", "across", "the", "lysosomal", "membrane", "and", "severe", "psychomotor", "retardation.", "Random", "linkage", "analysis", "of", "a", "sample", "of", "27", "Finnish", "families", "allowed", "us", "to", "localize", "the", "SD", "locus", "to", "the", "long", "arm", "of", "chromosome", "6.", "The", "highest", "lod", "score", "of", "8.95", "was", "obtained", "with", "a", "microsatellite", "marker", "of", "locus", "D6S286", "at", "theta", "=", ".00.", "Evidence", "for", "linkage", "disequilibrium", "was", "observed", "between", "the", "SD", "locus", "and", "the", "alleles", "of", "three", "closely", "linked", "markers,", "suggesting", "that", "the", "length", "of", "the", "critical", "region", "for", "the", "SD", "locus", "is", "in", "the", "order", "of", "190", "kb." ]
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The genetic locus for free sialic acid storage disease maps to the long arm of chromosome 6. Salla disease (SD), or adult-type free sialic acid storage disease, is an autosomal recessive lysosomal storage disorder characterized by impaired transport of free sialic acid across the lysosomal membrane and severe psychomotor retardation. Random linkage analysis of a sample of 27 Finnish families allowed us to localize the SD locus to the long arm of chromosome 6. The highest lod score of 8.95 was obtained with a microsatellite marker of locus D6S286 at theta = .00. Evidence for linkage disequilibrium was observed between the SD locus and the alleles of three closely linked markers, suggesting that the length of the critical region for the SD locus is in the order of 190 kb.
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7728155
[ "Mitochondrial", "acetoacetyl-coenzyme", "A", "thiolase", " ", "gene:", "a", "novel", "68-bp", "deletion", "involving", "3'", "splice", "site", "of", "intron", "7,", "causing", "exon", "8", "skipping", "in", "a", "Caucasian", "patient", "with", "beta-ketothiolase", "deficiency." ]
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Mitochondrial acetoacetyl-coenzyme A thiolase gene: a novel 68-bp deletion involving 3' splice site of intron 7, causing exon 8 skipping in a Caucasian patient with beta-ketothiolase deficiency.
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