Abstracts

Rationale: Exon-level deletion/duplication analysis enables the detection of a significant number of pathogenic variants and is an indispensable part of a comprehensive genetic analysis for epilepsy-related disorders. Studies demonstrate that pathogenic copy number variations (CNVs) account for 5% of patients with epilepsy-related disorders by chromosomal microarray (CMA) (Scheffer et al, Nat Rev Neurol. 2014, 10(9):490-1). However, this rate may be an underestimate if based on studies using CMA without enhanced coverage of epilepsy-related genes. For example, pathogenic multi-gene CNVs of the sodium voltage-gated channel gene cluster (SCN1A, SCN2A, SCN3A) located at 2q24.3 are commonly reported in association with neonatal seizures; however, single and partial gene CNVs in these genes have also been reported in patients with epilepsy, but may be missed by CMA. Methods: We conducted a retrospective study to assess the frequency and type of pathogenic CNVs detected by exon-level array CGH and next generation sequencing of up to 70 genes associated with epilepsy-related disorders in 9311 patients with epilepsy-related disorders. The array was designed to cover most coding regions of the investigated genes, but probe coverage was increased upstream and downstream of genes that are commonly involved in recurrent microdeletion/microduplication syndromes Results: A total of 186 CNVs were identified; 36.0% (67/186) included one or two exons, 25.3% (47/186) included three or more exons, 16.1% (30/186) included a whole gene, and 22.6% (42/186) involved multiple genes. Pathogenic CNVs were identified in 9.3% (137/1470) of positive cases in this cohort. A small number of positive cases (4%; 5/137), had both a pathogenic CNV and a sequencing variant in a single recessive gene. Additionally, we identified single pathogenic CNVs in recessive genes that may or may not contribute to the phenotype, as no second variant was identified (32/186). CNVs accounted for a notable proportion of positive cases in certain genes, including: CLN3 (100%, 4/4), MEF2C (57.1%, 4/7), GRIN2A (25%, 5/20), PRRT2 (15.5%, 9/58), CDKL5 (13.1%, 13/99), STXBP1 (9.8%, 6/61), TSC2 (9.5%, 11/116), KCNQ2 (9.4%, 15/159), TSC1 (6.1%, 3/49), SCN1A (4.1%, 13/319), and PCDH19 (4%, 3/74). The majority of positive findings reported for CLN3 and MEF2C were CNVs although the number of positive cases for these genes was small. Additionally, one or more pathogenic CNVs were observed in the GABRG2, MFSD8, PNKP, and TPP1 genes in this cohort; no pathogenic CNVs have been previously identified in these genes to our knowledge. Partial gene CNVs represented 61.3% (114/186) of all CNVs detected in this cohort. Multigenic CNVs involved genes known to be part of microdeletion/duplication syndromes such as UBE3A/Prader-Willi/Angelman region (20), SCN1A/SCN2A (9), KCNQ2/CHRNA4 (6), and CHRNA7/15q13.3 (4) Conclusions: Our data demonstrate the utility of deletion/duplication testing as part of a comprehensive genetic analysis for patients with epilepsy-related disorders. This is especially true for partial gene and exon-level CNVs, which may be missed by genome-wide array CGH. Funding: None