title: Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Bayram
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Coban Akdemir
authors.forename: Elif Ozdamar
authors.initials: EO
authors.lastname: Yilmaz
authors.forename: Gulsen Akay
authors.initials: GA
authors.lastname: Tayfun
authors.forename: Hatip
authors.initials: H
authors.lastname: Aydin
authors.forename: Deniz
authors.initials: D
authors.lastname: Torun
authors.forename: Sevcan Tug
authors.initials: ST
authors.lastname: Bozdogan
authors.forename: Alper
authors.initials: A
authors.lastname: Gezdirici
authors.forename: Sedat
authors.initials: S
authors.lastname: Isikay
authors.forename: Mehmed M
authors.initials: MM
authors.lastname: Atik
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.forename: Ayman W
authors.initials: AW
authors.lastname: El-Hattab
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Ali
authors.initials: A
authors.lastname: Karaman
authors.forename: Tamer
authors.initials: T
authors.lastname: Celik
authors.forename: Ozge Ozalp
authors.initials: OO
authors.lastname: Yuregir
authors.forename: Timur
authors.initials: T
authors.lastname: Yildirim
authors.forename: Ilhan A
authors.initials: IA
authors.lastname: Bayhan
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tuysuz
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005190:Family; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D014421:Turkey