title: Exome Sequencing Identifies a Dominant TNNT3 Mutation in a Large Family with Distal Arthrogryposis.
abstract: Distal arthrogryposis (DA) is a group of rare, clinically and genetically heterogeneous disorders primarily characterized by congenital contractures of the distal limb joints without a neuromuscular disease. Mutations in at least 8 different genes have been shown to cause DA. Here, we report a 4-generation Indian family with 18 affected members presenting variable features of camptodactyly, brachydactyly, syndactyly, decreased flexion palmar creases, ulnar deviation of the hands, sandal gaps and club feet. We undertook exome sequencing of 3 distantly related affected individuals. Bioinformatics filtering revealed a known pathogenic missense mutation c.188G>A (p.Arg63His) in TNNT3 in all 3 affected individuals that segregated with the phenotype. The affected individuals exhibit significant phenotypic variability. This study demonstrates the value of exome sequencing helping to define the causative variant in genetically heterogeneous disorders.
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Daly
authors.affiliation: Pediatric Orthopedics Services, Department of Orthopedics, Manipal, India.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Shah
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Beverley
authors.initials: B
authors.lastname: Anderson
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhaskar
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Nada
authors.initials: N
authors.lastname: Al-Sheqaih
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Abdul
authors.initials: A
authors.lastname: Mueed Bidchol
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK ; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Katta M
authors.initials: KM
authors.lastname: Girisha
keywords: Distal arthrogryposis; Sheldon-Hall syndrome; TNNT3