Detection of known genomic regions and intragenic copy-number changes by an expanded exon-targeted array with comprehensive coverage of genes implicated in autism spectrum disorders (ASDs) and intellectual disability (ID). S. W. Cheung1, P. Liu1, T. Gambin1, S. Gu1, P. Hixson1, C. Shaw1, W. Bi1, A. Breman1, J. Smith1, M. Haeri1, A. N. Pursley1, S. Lalani1,2, C. Bacino1,2, A. L. Beaudet1,2, J. R. Lupski1,2, P. Stankiewicz1, A. Patel1 1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX,; 2) Department of Pediatrics, Baylor College of Medicine, Houston, TX.

   With the rapid developments of whole- genome analysis techniques, an unprecedented opportunity to identify disease-causing genes for etiologically heterogenous conditions such as autism spectrum disorders (ASDs) and intellectual disability (ID) has become available. Multiple studies have now documented an excess of rare copy-number variants (CNVs) including exonic CNVs in patients with ASDs and ID. One strategy has been to focus on genes in shared pathways related to neuronal signaling and development, synapse function and chromatin regulation. As a result, we recently expanded our custom-designed oligo array to include >4800 disease or candidate genes with exon coverage and 60K SNP oligos. More specifically, coverage for all 50 genomic regions and 97% (120) of the 124 genes implicated in ASDs and ID [PMID: 24768552, table S6A and S6B], with an average of 85.65 oligonucleotide probes per gene, is included. 6499 patients have been evaluated by this array with indications provided for 4944 cases. 3016 patients (61%) studied had a clinical indication of developmental delay (DD), ID or autism. Overall, CNVs encompassing or disrupting a single gene were identified in 1536 cases (24%); 47% of these cases (726/1536) had an indication related with cognitive impairment. Examples of known pathogenic CNVs (both deletion and duplication) identified include the following genomic regions: 1q21 (16); DG (39); PWS/AS (21); 16p11.2 (24) and 15q13.3 (14). Examples of disease-causing exonic CNVs detected include: MECP2 (Rett syndrome and MECP2 Duplication syndrome); SHANK3 (Phelan-McDermid syndrome); and DMD (Duchenne muscular dystrophy). The more commonly observed CNVs in this cohort affecting known and candidate genes for ASDs/ID include RBFOX1 (27); NRXN1 (9); PARK2 (8); IMMP2L (25); AHI1 (4) and CNTN4 (4). Detection of recurring intragenic CNVs in this patient population will support reclassifying candidate genes implicated in neurodevelopmental disorders as disease-causing genes. For example, of the 10 cases with exonic CNVs in the candidate gene, ANKRD11, nine had indications of DD and ASDs. In summary, our approach not only enabled detection of known genetic conditions but has the potential to elucidate new disease genes. Additionally, the comprehensive coverage of genes implicated in ASDs and ID allows detection of exonic CNVs thus improving the diagnostic capability of this patient population through utilization of an already available clinical assay.

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