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Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

By Maria Kousi, Onuralp Söylemez, Aysegül Ozanturk, Sebastian Akle, Irwin Jungreis, Jean Muller, Christopher Cassa, Harrison Brand, Jill Anne Mokry, Maxim Y Wolf, Azita Sadeghpour, Kelsey McFadden, Richard A Lewis, Michael E. Talkowski, Hélène Dollfus, Manolis Kellis, Erica E Davis, Shamil R. Sunyaev, Nicholas Katsanis

Posted 05 Jul 2018
bioRxiv DOI: 10.1101/362707 (published DOI: 10.1038/s41588-020-0707-1)

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remains unclear. We performed a systematic secondary-variant burden analysis of two independent Bardet-Biedl syndrome (BBS) cohorts with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants compared to either population controls or to a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes, a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model paradigm for secondary-variant burden analysis in recessive disorders.

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