|Title||Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Bayram 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 Authors||Lupski JR|
|Journal||J Clin Invest|
|Date Published||2016 Feb|
|Keywords||Arthrogryposis, 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 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.
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 Journal||J Clin Invest|
|PubMed Central ID||PMC4731160|
|Grant List||U54 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