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Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin.

TitleMolecular etiology of arthrogryposis in multiple families of mostly Turkish origin.
Publication TypeJournal Article
Year of Publication2016
AuthorsBayram Y, Karaca E, Akdemir ZCoban, Yilmaz EOzdamar, Tayfun GAkay, Aydin H, Torun D, Bozdogan STug, Gezdirici A, Isikay S, Atik MM, Gambin T, Harel T, El-Hattab AW, Charng W-L, Pehlivan D, Jhangiani SN, Muzny DM, Karaman A, Celik T, Yuregir OOzalp, Yildirim T, Bayhan IA, Boerwinkle E, Gibbs RA, Elcioglu N, Tuysuz B
Secondary AuthorsLupski JR
JournalJ Clin Invest
Date Published2016 Feb
KeywordsArthrogryposis, Exome, Family, Female, Genome-Wide Association Study, Humans, Male, Turkey

BACKGROUND: 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.

METHODS: We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families.

RESULTS: Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic ╬│ 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.

CONCLUSION: 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.

FUNDING: 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.

Alternate JournalJ Clin Invest
PubMed ID26752647
PubMed Central IDPMC4731160
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
T32 GM07526 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States