title: Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Tracy
authors.initials: T
authors.lastname: Tucker
authors.affiliation: 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.
authors.forename: Farah R
authors.initials: FR
authors.lastname: Zahir
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
authors.forename: Malachi
authors.identifier: 000000026388446X
authors.initials: M
authors.lastname: Griffith
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
authors.forename: Allen
authors.initials: A
authors.lastname: Delaney
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chai
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Erica
authors.initials: E
authors.lastname: Tsang
authors.affiliation: CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.affiliation: CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Marra
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Patrice
authors.initials: P
authors.lastname: Eydoux
authors.affiliation: 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.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Langlois
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: 1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada [2] Child & Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D002648:Child; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations / Q000235:genetics; D015342:DNA Probes / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009679:Nuclear Family; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015342:DNA Probes