Costain, GregoryWalker, SusanArgiropoulos, BobBaribeau, Danielle ABassett, Anne SBoot, ErikDevriendt, KoenKellam, BarbaraMarshall, Christian RPrasad, AparnaSerrano, Moises AStavropoulos, D. JTwede, HopeVermeesch, Joris RVorstman, Jacob A SScherer, Stephen W2019-02-102019-02-102019-02-07Journal of Neurodevelopmental Disorders. 2019 Feb 07;11(1):3http://hdl.handle.net/1880/109893https://doi.org/10.11575/PRISM/44518Abstract 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.Journal Article2019-02-10enThe Author(s).https://doi.org/10.1186/s11689-019-9263-3