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

J Neurodev Disord. 2019 Feb 7;11(1):3. doi: 10.1186/s11689-019-9263-3.


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.

Keywords: ADHD; Autism; Copy number variation; DMXL2; GRIK5; Genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Autism Spectrum Disorder / genetics
  • Child
  • DNA Copy Number Variations*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Neurodevelopmental Disorders / genetics*
  • Pedigree
  • Whole Genome Sequencing*


  • Adaptor Proteins, Signal Transducing
  • DMXL2 protein, human
  • Nerve Tissue Proteins