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

TitleThe Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.
Publication TypeJournal Article
Year of Publication2019
AuthorsPehlivan, D, Bayram, Y, Gunes, N, Akdemir, ZCoban, Shukla, A, Bierhals, T, Tabakci, B, Sahin, Y, Gezdirici, A, Fatih, JM, Gulec, EYilmaz, Yesil, G, Punetha, J, Ocak, Z, Grochowski, CM, Karaca, E, Albayrak, HMutlu, Radhakrishnan, P, Erdem, HBagis, Sahin, I, Yildirim, T, Bayhan, IA, Bursali, A, Elmas, M, Yuksel, Z, Ozdemir, O, Silan, F, Yildiz, O, Yesilbas, O, Isikay, S, Balta, B, Gu, S, Jhangiani, SN, Doddapaneni, H, Hu, J, Muzny, DM, Boerwinkle, E, Gibbs, RA, Tsiakas, K, Hempel, M, Girisha, KMohan, Gul, D, Posey, JE, Elcioglu, NH, Tuysuz, B, Lupski, JR
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2019 Jul 03
KeywordsAdolescent, Adult, Arthrogryposis, Child, Child, Preschool, Cohort Studies, Connectin, DNA Copy Number Variations, Exome Sequencing, Female, Genetic Markers, Genomics, Gestational Age, Humans, Infant, Infant, Newborn, Male, Mosaicism, Multifactorial Inheritance, Mutation, Pedigree, Ryanodine Receptor Calcium Release Channel, Vesicular Transport Proteins, Young Adult

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.

Alternate JournalAm J Hum Genet
PubMed ID31230720
PubMed Central IDPMC6612529
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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