title: Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes.
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. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Canada's Michael Smith Genome Sciences Center, Vancouver, British Columbia, Canada. farahz@cfri.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. farahz@cfri.ca.
authors.forename: Farah R
authors.initials: FR
authors.lastname: Zahir
authors.affiliation: Provincial Medical Genetics Programme, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Tracy
authors.initials: T
authors.lastname: Tucker
authors.affiliation: Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario y Politécnico La Fe. Valencia, Valencia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mayo
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Brown
authors.affiliation: Canada's Michael Smith Genome Sciences Center, Vancouver, British Columbia, Canada.
authors.forename: Emilia L
authors.initials: EL
authors.lastname: Lim
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Canada's Michael Smith Genome Sciences Center, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D008297:Male; D009154:Mutation; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011159:Population Surveillance
chemical_list: C547777:JARID2 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; D063151:Polycomb Repressive Complex 2
keywords: ARID1B; ARID2; ARID4B; CHD6; CHD7; JARID2; JMJDIC; KDM3A; MEF2C; UBE2A; epigenetics; intellectual disability; intragenic CNVs