Journal Article

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Twede, Hope, Marshall, Christian R., Baribeau, Danielle A., Kellam, Barbara, Serrano, Moises A., Walker, Susan, Bassett, Anne S., Vermeesch, Joris R., Scherer, Stephen W., Stavropoulos, D. James, Argiropoulos, Bob, Devriendt, Koen, Costain, Gregory, Boot, Erik, Vorstman, Jacob A. S., Prasad, Aparna

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adaptor Proteins, Signal Transducing - genetics / ADHD / Adult / Autism / Autism Spectrum Disorder - genetics / Biomedical and Life Sciences / Biomedicine / Child / Copy number / Copy number variation / Development and progression / DMXL2 / DNA Copy Number Variations / DNA sequencing / Etiology / Etiology (Medicine) / Families & family life / Female / Gene deletion / Genes / Genetic aspects / Genetic diversity / Genome sequencing / Genomes / Genomics / GRIK5 / Human Genetics / Humans / Intellectual disabilities / Laboratories / Male / Medical research / Middle Aged / Mutation / Nerve Tissue Proteins - genetics / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurology / Neuropsychology / Neurosciences / Novels / Pediatrics / Pedigree / Phenotypes / Psychiatry / Schizophrenia / Software / Whole Genome Sequencing