Journal Article

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Karaca, Ender, Muzny, Donna M., Tayfun, Gulsen Akay, Yuregir, Ozge Ozalp, Yildirim, Timur, Torun, Deniz, Harel, Tamar, Yilmaz, Elif Ozdamar, Boerwinkle, Eric, Aydin, Hatip, Jhangiani, Shalini N., Lupski, James R., Atik, Mehmed M., Bozdogan, Sevcan Tug, Tuysuz, Beyhan, Gezdirici, Alper, El-Hattab, Ayman W., Gibbs, Richard A., Coban Akdemir, Zeynep, Bayram, Yavuz, Bayhan, Ilhan A., Celik, Tamer, Karaman, Ali, Isikay, Sedat, Charng, Wu-Lin, Elcioglu, Nursel, Gambin, Tomasz, Pehlivan, Davut

2016

Overview

Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.

• Publisher: American Society for Clinical Investigation
• Subject: Arthrogryposis / Arthrogryposis - genetics / Arthrogryposis - pathology / Biomedical research / Clinical Medicine / Congenital diseases / Development and progression / Disease / Exome / Exome sequencing / Family / Female / Gene expression / Genes / Genetic aspects / Genome-Wide Association Study / Genomics / Genotype / Health aspects / Humans / Identification and classification / Male / Methods / Mutation / Proteins / Turkey