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The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance

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dc.contributor.authorPehlivan, Davut
dc.contributor.authorBayram, Yavuz
dc.contributor.authorGunes, Nilay
dc.contributor.authorAkdemir, Zeynep Coban
dc.contributor.authorShukla, Anju
dc.contributor.authorBierhals, Tatjana
dc.contributor.authorTABAKCI, BURCU
dc.contributor.authorSahin, Yavuz
dc.contributor.authorGezdirici, Alper
dc.contributor.authorFatih, Jawid M.
dc.contributor.authorGulec, Elif Yilmaz
dc.contributor.authorYEŞİL, GÖZDE
dc.contributor.authorPunetha, Jaya
dc.contributor.authorOcak, Zeynep
dc.contributor.authorGrochowski, Christopher M.
dc.contributor.authorKaraca, Ender
dc.contributor.authorAlbayrak, Hatice Mutlu
dc.contributor.authorRadhakrishnan, Periyasamy
dc.contributor.authorErdem, Haktan Bagis
dc.contributor.authorSahin, Ibrahim
dc.contributor.authorYildirim, Timur
dc.contributor.authorBayhan, Ilhan A.
dc.contributor.authorBursali, Aysegul
dc.contributor.authorElmas, Muhsin
dc.contributor.authorYuksel, Zafer
dc.contributor.authorOzdemir, Ozturk
dc.contributor.authorSilan, Fatma
dc.contributor.authorYildiz, Onur
dc.contributor.authorYesilbas, Osman
dc.contributor.authorIsikay, Sedat
dc.contributor.authorBalta, Burhan
dc.contributor.authorGu, Shen
dc.contributor.authorJhangiani, Shalini N.
dc.contributor.authorDoddapaneni, Harsha
dc.contributor.authorHu, Jianhong
dc.contributor.authorMuzny, Donna M.
dc.contributor.authorBoerwinkle, Eric
dc.contributor.authorGibbs, Richard A.
dc.contributor.authorTsiakas, Konstantinos
dc.contributor.authorHempel, Maja
dc.contributor.authorGirisha, Katta Mohan
dc.contributor.authorGul, Davut
dc.contributor.authorPosey, Jennifer E.
dc.contributor.authorElcioglu, Nursel H.
dc.contributor.authorTuysuz, Beyhan
dc.contributor.authorLupski, James R.
dc.contributor.institutionauthorYEŞİL, GÖZDE
dc.date.accessioned2019-11-17T23:41:02Z
dc.date.available2019-11-17T23:41:02Z
dc.date.issued2019-07-03
dc.description.abstractArthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.
dc.identifier.citationPehlivan D., Bayram Y., Gunes N., Akdemir Z. C. , Shukla A., Bierhals T., TABAKCI B., Sahin Y., Gezdirici A., Fatih J. M. , et al., -The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance-, AMERICAN JOURNAL OF HUMAN GENETICS, cilt.105, ss.132-150, 2019
dc.identifier.doi10.1016/j.ajhg.2019.05.015
dc.identifier.pubmed31230720
dc.identifier.scopus85068067184
dc.identifier.urihttps://hdl.handle.net/20.500.12645/10311
dc.identifier.wosWOS:000473723000011
dc.language.isoen
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleThe Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
dc.typeArticle
dspace.entity.typePublication
local.avesis.id1385f83c-3e33-4116-ac67-7fd32c705edd
local.org.facultyTıp Fakültesi
local.publication.isinternational1
relation.isAuthorOfPublicationb653abbc-327a-4b3b-a227-f3344d8d6b70
relation.isAuthorOfPublication.latestForDiscoveryb653abbc-327a-4b3b-a227-f3344d8d6b70
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