Abstract：
:Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the NOGGIN gene has been shown to be responsible for the disorder. However, in a cohort of six probands with multiple-synostosis syndrome, only one was found to be heterozygous for a NOGGIN mutation (W205X). Linkage studies involving the four-generation family of one of the mutation-negative patients excluded the NOGGIN locus, providing genetic evidence of locus heterogeneity. In this family, polymorphic markers flanking the GDF5 locus were found to cosegregate with the disease, and sequence analysis demonstrated that affected individuals in the family were heterozygous for a novel missense mutation that predicts an R438L substitution in the GDF5 protein. Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C, the protein encoded by the multiple-synostosis-syndrome allele was secreted as a mature GDF5 dimer. These data establish locus heterogeneity in multiple-synostosis syndrome and demonstrate that the disorder can result from mutations in either the NOGGIN or the GDF5 gene.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Dawson K,Seeman P,Sebald E,King L,Edwards M,Williams J 3rd,Mundlos S,Krakow Ddoi
10.1086/503204subject
Has Abstractpub_date
2006-04-01 00:00:00pages
708-12issue
4eissn
0002-9297issn
1537-6605pii
S0002-9297(07)63708-2journal_volume
78pub_type
杂志文章abstract：:Whole-genome sequencing (WGS) studies are being widely conducted in order to identify rare variants associated with human diseases and disease-related traits. Classical single-marker association analyses for rare variants have limited power, and variant-set-based analyses are commonly used by researchers for analyzing...
journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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更新日期：1995-01-01 00:00:00
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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更新日期：1977-01-01 00:00:00
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journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/302588
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journal_title：American journal of human genetics
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doi：
更新日期：1994-08-01 00:00:00
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journal_title：American journal of human genetics
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doi：
更新日期：1991-02-01 00:00:00
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
pub_type： 杂志文章
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