Browsing by Author "Costain, Gregory"

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    Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders
    (2019-02-07) Costain, Gregory; Walker, Susan; Argiropoulos, Bob; Baribeau, Danielle A; Bassett, Anne S; Boot, Erik; Devriendt, Koen; Kellam, Barbara; Marshall, Christian R; Prasad, Aparna; Serrano, Moises A; Stavropoulos, D. J; Twede, Hope; Vermeesch, Joris R; Vorstman, Jacob A S; Scherer, Stephen W
    Abstract Background Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. Methods We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. Results We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. Conclusions Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.