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The pathogenicity of copy number variants in children with intellectual disability Zahir, Farah R

Abstract

Intellectual disability affects 1-3% of individuals globally, and, for half the cases, the cause is unknown. Recent studies using whole genome microarray genomic hybridization have shown that submicroscopic genomic imbalance causes intellectual disability in at least 10% of idiopathic cases with normal conventional cytogenetic analysis. I established genotype-phenotype correlations for de novo copy number variants detected by previous whole genome array genome hybridization studies performed by our group in children with intellectual disability. These genotype-phenotype correlations show that genomic imbalance of genes belonging to the epigenetic regulatory category, among others, are causative of intellectual disability. I hypothesized that dosage changes in the broad functional category of genes encoding epigenetic regulatory proteins are more likely to be pathogenic for intellectual disability than dosage changes in other kinds of genes. Epigenetic regulatory proteins include those with DNA methylation, histone modification or chromatin remodeling activity. I have selected all known genes encoding epigenetic regulatory proteins and defined probes to interrogate these candidate genes for copy number alteration as part of a custom targeted microarray design that selectively investigates all candidate genes associated with intellectual disability. We have conducted comparative genome hybridization on 177 patients with idiopathic intellectual disability using this array and on both normal parents of each affected child. We identified and independently validated 16 cases with de novo CNVs involving the epigenetic regulatory candidates. 7 of the 16 CNVs involve the same exon of the JARID2 gene, while the other 9 CNVs affect different genes. I discuss genotype-phenotype correlations for these cases and show that epigenetic perturbation by way of disruption of genes that encode epigenetic regulators is an important cause for intellectual disability.

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