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Genotype‐phenotype relationships in Freeman–Sheldon syndrome
Author(s) -
Beck Anita E.,
McMillin Margaret J.,
Gildersleeve Heidi I. S.,
Shively Kathryn M. B.,
Tang Andy,
Bamshad Michael J.
Publication year - 2014
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36762
Subject(s) - phenotype , genotype , biology , muscle contracture , arthrogryposis , genetics , gene , anatomy
Distal arthrogryposis (DA) syndromes are a group of disorders characterized by multiple congenital contractures. DA type 2A (DA2A or Freeman–Sheldon syndrome), caused by mutations in MYH3 , is typically considered the most severe of the DA syndromes. However, there is wide phenotypic variability among individuals with DA2A. We characterized genotype‐phenotype relationships in 46 families with DA2A. MYH3 mutations were found in 43/46 (93%) kindreds, with three mutations (p.T178I, p.R672C, and p.R672H) explaining 39/43 (91%) of cases. Phenotypic severity varied significantly by genotype ( P = 0.0055). Individuals with p.T178I were the most severely affected with both facial contractures and congenital scoliosis. Classification of individuals with DA2A into phenotypic groups of varying severity should facilitate providing families with more accurate information about natural history and suggests that individuals might benefit from personalized medical management motivated by MYH3 genotype. © 2014 Wiley Periodicals, Inc.