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Eur J Hum Genet. 2014 Jun;22(6):792-800. doi: 10.1038/ejhg.2013.248. Epub 2013 Nov 20.

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes.

Author information

1
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
2
1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada [2] Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
3
Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
4
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
5
CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.
6
1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada [2] Provincial Medical Genetics Programme, Children's & Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada.
7
1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada [2] Child & Family Research Institute, Vancouver, British Columbia, Canada.

Abstract

Intellectual disability affects about 3% of individuals globally, with∼50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copy-number variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis.

PMID:
24253858
PMCID:
PMC4023222
DOI:
10.1038/ejhg.2013.248
[Indexed for MEDLINE]
Free PMC Article
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