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

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. Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

Davut Pehlivan, Yavuz Bayram, Nilay Gunes, Zeynep Coban Akdemir, Anju Shukla, Tatjana Bierhals, Burcu Tabakci, Yavuz Sahin, Alper Gezdirici, Jawid M Fatih, Elif Yilmaz Gulec, Gozde Yesil, Jaya Punetha, Zeynep Ocak, Christopher M Grochowski, Ender Karaca, Hatice Mutlu Albayrak, Periyasamy Radhakrishnan, Haktan Bagis Erdem, Ibrahim Sahin, Timur Yildirim, Ilhan A Bayhan, Aysegul Bursali, Muhsin Elmas, Zafer Yuksel, Ozturk Ozdemir, Fatma Silan, Onur Yildiz, Osman Yesilbas, Sedat Isikay, Burhan Balta, Shen Gu, Shalini N Jhangiani, Harsha Doddapaneni, Jianhong Hu, Donna M Muzny, Baylor-Hopkins Center for Mendelian Genomics, Eric Boerwinkle, Richard A Gibbs, Konstantinos Tsiakas, Maja Hempel, Katta Mohan Girisha, Davut Gul, Jennifer E Posey, Nursel H Elcioglu, Beyhan Tuysuz, James R Lupski. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance. American journal of human genetics. 2019 Jul 03;105(1):132-150

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PMID: 31230720

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