Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes

Am J Med Genet A. 2016 Nov;170(11):2916-2926. doi: 10.1002/ajmg.a.37669.


The disruption of genes involved in epigenetic regulation is well known to cause Intellectual Disability (ID). We reported a custom microarray study that interrogated among others, the epigenetic regulatory gene-class, at single exon resolution. Here we elaborate on identified intragenic CNVs involving epigenetic regulatory genes; specifically discussing those in three genes previously unreported in ID etiology-ARID2, KDM3A, and ARID4B. The changes in ARID2 and KDM3A are likely pathogenic while the ARID4B variant is uncertain. Previously, we found a CNV involving only exon 6 of the JARID2 gene occurred apparently de novo in seven patients. JARID2 is known to cause ID and other neurodevelopmental conditions. However, exon 6 of this gene encodes one of a series of repeated motifs. We therefore, investigated the impact of this variant in two cohorts and present a genotype-phenotype assessment. We find the JARID2 exon 6 CNV is benign, with a high population frequency (>14%), but nevertheless could have a contributory effect. We also present results from an interrogation of the exomes of 2,044 patients with neurocognitive phenotypes for the incidence of potentially damaging mutation in the epigenetic regulatory gene-class. This paper provides a survey of the fine-scale CNV landscape for epigenetic regulatory genes in the context of ID, describing likely pathogenic as well as benign single exon imbalances. © 2016 Wiley Periodicals, Inc.

Keywords: ARID1B; ARID2; ARID4B; CHD6; CHD7; JARID2; JMJDIC; KDM3A; MEF2C; UBE2A; epigenetics; intellectual disability; intragenic CNVs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • DNA Copy Number Variations*
  • DNA Methylation
  • Epigenesis, Genetic*
  • Exons*
  • Female
  • Gene Deletion
  • Gene Duplication
  • Gene Expression Regulation*
  • Genetic Association Studies
  • Genotype
  • Humans
  • Intellectual Disability / epidemiology
  • Intellectual Disability / genetics*
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Male
  • Mutation
  • Phenotype
  • Polycomb Repressive Complex 2 / genetics
  • Population Surveillance


  • JARID2 protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3A protein, human
  • Polycomb Repressive Complex 2