title: Genotype-phenotype relationships in Freeman-Sheldon syndrome.
abstract: 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.
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Anita E
authors.initials: AE
authors.lastname: Beck
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: McMillin
authors.forename: Heidi I S
authors.initials: HI
authors.lastname: Gildersleeve
authors.forename: Kathryn M B
authors.initials: KM
authors.lastname: Shively
authors.forename: Andy
authors.initials: A
authors.lastname: Tang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003394:Craniofacial Dysostosis / Q000175:diagnosis* / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D011859:Radiography; D013131:Spine / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D003598:Cytoskeletal Proteins; C510594:MYH3 polypeptide, human
keywords: arthrogryposis; clubfoot; congenital foot deformities; congenital hand deformities; congenital limb deformities; congenital lower extremity deformities; congenital upper extremity deformities; contracture; distal arthrogryposis; distal arthrogryposis type 2A; human MYH3 polypeptide; muscle; musculoskeletal abnormalities; myosin heavy chains; skeletal muscle