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

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. 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. 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. 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.

• Publication year

  2019

• Venue

  Journal of Neurodevelopmental Disorders

• Publication date

  2019-02-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s11689-019-9263-3PMID 30732576PMCID 6366120
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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