Abstracts

Rationale: Chromosome microarray-based genomic copy-number analysis (CMA) can interrogate the entire genome, allowing rapid discovery of disease-associated copy number variants (CNVs). Its diagnostic yield is approximately 15%-20% in patients with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). More recent studies have demonstrated the important role of CMA in the discovery of both novel and recurrent epilepsy-associated CNVs in patients with epilepsy, although determining their significance may be challenging. In patients with epilepsy and additional neurodevelopmental disorders or intractable epilepsy of unknown origin the diagnostic accuracy of CMA may be as high as 15%. In this report we describe the results of performing microarray analysis on 706 children with unexplained epilepsy plus other neurological and/or congenital defects. Methods: We performed a retrospective chart review on clinical and genetic aspects of CNVs identified in 706 patients with epilepsy associated with DD/ID, ASD and/ or multiple congenital anomalies (MCA), seen at the Vancouver BC Children's Hospital from 2009 to 2014. All patients had CMA performed using Affymetrix Genome-Wide Human SNP Array 6.0 or CytoScanHD®. Results: Abnormal CMA results were identified in 192 out of 706 children with epilepsy plus. 115/706 (16.3%) patients had variants of unknown significance VUS, defined as CNVs not previously identified in normal or pathogenic database. 77/706 (10.9%) patients had CNVs determined pathogenic or likely responsible for their clinical features based on characteristics of CNV, identification of recognized recurrent microdeletion/duplication syndromes, and/or overlap with similarly reported case(s). This group included 33 patients that had CNVs in previously reported genomic "hotspots" that predispose to epilepsy, including deletions in 1q21.1 (n=1), 15q11.2 (n=7), 15q13.3 (n=4), 15q11-q13 (n=4), 16p11.2 (n=7), and 16p13.11(n=10). Other important recurring CNVs identified included recurrent 17q12 duplication (2=4) and 22q13.3 deletion (Phelan-McDermid Syndrome) (n=4). One of the four 22q13.3 deletion patients had treatment resistant epilepsy and a small deletion (47kb) of SHANK3 gene. 33 patients had multiple CNVs, of this group, 12 had two or more VUS and 9 had both VUS and pathogenic CNVs. Conclusions: This review supports the high diagnostic yield of performing CMA in children with unexplained epilepsy. CMA revealed mutations in epilepsy "hotspots", and known microdeletion syndromes like Phelan-McDermid syndrome (22q13.3 deletion). Examination of CNVs also plays an important role in the identification of possible epilepsy genes i.e. SHANK3 mutations in patients with 22q13.3 deletions.