title: Spectrum of mutations that cause distal arthrogryposis types 1 and 2B.
abstract: The distal arthrogryposis (DA) syndromes are a group of disorders characterized by non-progressive congenital contractures of the limbs. Mutations that cause distal arthrogryposis syndromes have been reported in six genes, each of which encodes a component of the contractile apparatus of skeletal myofibers. However, these reports have usually emanated from gene discovery efforts and thus potentially bias estimates of the frequency of pathogenic mutations at each locus. We characterized the spectrum of pathogenic variants in a cohort of 153 cases of DA1 (n = 48) and DA2B (n = 105). Disease-causing mutations in 56/153 (37%) kindreds including 14/48 (29%) with DA1 and 42/105 (40%) with DA2B were distributed nearly equally across TNNI2, TNNT3, TPM2, and MYH3. In TNNI2, TNNT3, and TPM2 the same mutation caused DA1 in some families and DA2B in others. We found no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. Collectively, the substantial overlap between phenotypic characteristics and spectrum of mutations suggests that DA1 and DA2B should be considered phenotypic extremes of the same disorder.
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. aebeck@uw.edu
authors: Anita E
authors: AE
authors: Beck
authors: Margaret J
authors: MJ
authors: McMillin
authors: Heidi I S
authors: HI
authors: Gildersleeve
authors: Phillip R
authors: PR
authors: Kezele
authors: Kathryn M
authors: KM
authors: Shively
authors: John C
authors: JC
authors: Carey
authors: Michael
authors: M
authors: Regnier
authors: Michael J
authors: MJ
authors: Bamshad
mesh_terms: D000293:Adolescent; D001176:Arthrogryposis / Q000235:genetics*; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D006801:Humans; D020125:Mutation, Missense; D017384:Sequence Deletion; D014335:Tropomyosin / Q000235:genetics; D019210:Troponin I / Q000235:genetics; D020107:Troponin T / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; C510594:MYH3 polypeptide, human; C518658:TNNI2 protein, human; C518660:TNNT3 protein, human; C518659:TPM2 protein, human; D014335:Tropomyosin; D019210:Troponin I; D020107:Troponin T
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