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

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Date
2019-07-03
Author
Jhangiani, Shalini N.
Boerwinkle, Eric
Gibbs, Richard A.
Tsiakas, Konstantinos
Hempel, Maja
Girisha, Katta Mohan
Gul, Davut
Posey, Jennifer E.
Elcioglu, Nursel H.
Tuysuz, Beyhan
Lupski, James R.
Ozdemir, Ozturk
Pehlivan, Davut
Bayram, Yavuz
Gunes, Nilay
Akdemir, Zeynep Coban
Shukla, Anju
Bierhals, Tatjana
TABAKCI, BURCU
Sahin, Yavuz
Gezdirici, Alper
Fatih, Jawid M.
YEŞİL, GÖZDE
Gulec, Elif Yilmaz
Punetha, Jaya
Ocak, Zeynep
Grochowski, Christopher M.
Karaca, Ender
Albayrak, Hatice Mutlu
Radhakrishnan, Periyasamy
Erdem, Haktan Bagis
Sahin, Ibrahim
Yildirim, Timur
Bayhan, Ilhan A.
Bursali, Aysegul
Elmas, Muhsin
Yuksel, Zafer
Silan, Fatma
Yildiz, Onur
Yesilbas, Osman
Isikay, Sedat
Balta, Burhan
Gu, Shen
Doddapaneni, Harsha
Hu, Jianhong
Muzny, Donna M.
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Article
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Abstract
Arthrogryposis 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.
Subject
Pehlivan 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
URI
https://hdl.handle.net/20.500.12645/10311
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  • PubMed İndeksli Yayın Koleksiyonu [3669]
  • Scopus İndeksli Yayınlar Koleksiyonu [4450]
  • Tıp Fakültesi [2546]
  • WoS İndeksli Yayınlar Koleksiyonu [5147]
  • Yayınlar - Eserler [9994]

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BEZMIALEM VAKIF UNIVERSITY

About us |Policies | Library | Contact us | Send Feedback | Sitemap | Admin

Bezmialem Vakıf Üniversitesi, Adnan Menderes Bulvarı Vatan Caddesi 34093 Fatih, İstanbul / TURKEY
Copyright © Bezmialem Vakıf Üniversitesi

Creative Commons Lisansı
Bezmialem Institutional Repository, Creative Commons Alıntı-GayriTicari-Türetilemez 4.0 Uluslararası Lisansı ile lisanslanmıştır.

OpenAccess@BVU

Support by  UNIREPOS