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Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
Name
362707v1.full.pdf
Description
Submitted version
Size
3.26 MB
Format
Adobe PDF
Checksum (MD5)
6b7a52f2216d342c360e270541668bd2
Author(s)
Kousi, Maria
Söylemez, Onuralp
Ozanturk, Aysegül
Mourtzi, Niki
Akle, Sebastian
Jungreis, Irwin
Muller, Jean
Cassa, Christopher A
Brand, Harrison
Mokry, Jill Anne
Date Issued
2020
Journal
Nature Genetics
Publisher
Springer Science and Business Media LLC
Version
Original manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
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DOI of Published Version
10.1038/s41588-020-0707-1
