@article {120,
	title = {Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy.},
	journal = {Nat Genet},
	volume = {52},
	year = {2020},
	month = {2020 11},
	pages = {1145-1150},
	abstract = {<p>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.</p>},
	keywords = {Alleles, Bardet-Biedl Syndrome, Cohort Studies, Exome, Genetic Variation, Humans},
	issn = {1546-1718},
	doi = {10.1038/s41588-020-0707-1},
	author = {Kousi, Maria and S{\"o}ylemez, Onuralp and Ozanturk, Ayseg{\"u}l and Mourtzi, Niki and Akle, Sebastian and Jungreis, Irwin and Muller, Jean and Cassa, Christopher A and Brand, Harrison and Mokry, Jill Anne and Wolf, Maxim Y and Sadeghpour, Azita and McFadden, Kelsey and Lewis, Richard A and Talkowski, Michael E and Dollfus, H{\'e}l{\`e}ne and Kellis, Manolis and Davis, Erica E and Sunyaev, Shamil R and Katsanis, Nicholas}
}
