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

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

Author information

1
Canada's Michael Smith Genome Sciences Center, Vancouver, British Columbia, Canada. farahz@cfri.ca.
2
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. farahz@cfri.ca.
3
Provincial Medical Genetics Programme, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada.
4
Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario y Politécnico La Fe. Valencia, Valencia, Spain.
5
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
6
Canada's Michael Smith Genome Sciences Center, Vancouver, British Columbia, Canada.
7
CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.

Abstract

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.

KEYWORDS:

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

PMID:
27748065
DOI:
10.1002/ajmg.a.37669
[Indexed for MEDLINE]

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