Tucker Tracy, Zahir Farah R, Griffith Malachi, Delaney Allen, Chai David, Tsang Erica, Lemyre Emmanuelle, Dobrzeniecka Sylvia, Marra Marco, Eydoux Patrice, Langlois Sylvie, Hamdan Fadi F, Michaud Jacques L, Friedman Jan M
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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.
Eur J Hum Genet. 2014 Jun;22(6):792-800. doi: 10.1038/ejhg.2013.248. Epub 2013 Nov 20.
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.
智力残疾在全球约3%的个体中存在，其中约50%为特发性。我们设计了一个外显子分辨率阵列，针对所有已知的亚微观染色体智力残疾综合征位点、智力残疾的致病基因以及潜在的候选基因，即所有编码谷氨酸受体和表观遗传调节因子的基因。利用该平台，我们对165个智力残疾三联体（患病儿童及其双亲均正常）进行了染色体微阵列分析。我们在32个三联体中鉴定并独立验证了36个新生拷贝数变化。总体而言，67%的已验证事件发生在基因内，仅涉及外显子1（根据我们的设计，其包括启动子序列）、外显子1和相邻外显子，或除外显子1之外的一个或多个外显子。36个拷贝数变异中有17个涉及已知会导致智力残疾的基因。其中11个，包括7个基因内变异，明显具有致病性（涉及STXBP1、SHANK3（3例患者）、IL1RAPL1、UBE2A、NRXN1、MEF2C、CHD7、15q24和9p24微缺失），2个可能具有致病性（PI4KA、DCX），2个不太可能具有致病性（GRIK2、FREM2），2个尚不清楚（ARID1B、15q22微缺失）。我们阵列鉴定出的12名基因组失衡个体接受了临床微阵列检测，其中6名结果正常。我们在先前未与智力残疾相关的基因中鉴定出新生拷贝数变异，并发现了标准临床诊断染色体微阵列分析检测限以下已知智力残疾基因的致病变异。
