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

Maria Kousi, Onuralp Söylemez, Aysegül Ozanturk, Niki Mourtzi, Sebastian Akle, Irwin Jungreis, Jean Muller, Christopher A. 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) 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 in patients with BBS compared with either population controls or 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 for secondary-variant burden analysis in recessive disorders.

Original languageEnglish (US)
Pages (from-to)1145-1150
Number of pages6
JournalNature Genetics
Volume52
Issue number11
DOIs
StatePublished - Nov 1 2020

ASJC Scopus subject areas

  • Genetics

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