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Wolf, Maxim

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Wolf, Maxim

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    Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
    (SpringerNature, 2018-07-05) Kousi, Maria; Söylemez, Onuralp; Ozanturk, Aysegül; Akle, Sebastian; Jungreis, Irwin; Muller, Jean-Francois; Cassa, Christopher; Brand, Harrison; Mokry, Jill Anne; Wolf, Maxim; Sadeghpour, Azita; McFadden, Kelsey; Lewis, Richard A.; Talkowski, Michael; Dollfus, Hélène; Kellis, Manolis; Davis, Erica E.; Sunyaev, Shamil; Katsanis, Nicholas
    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)1 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.