Abstracts

Rationale: Copy number variants (CNVs) contribute to the genetics of multiple neurodevelopmental disorders with complex inheritance, including genetic generalized epilepsy (GGE) and intellectual disability (ID). We examined whether CNVs were more common in those with a combination of ID and GGE (ID-GGE) than in those with either phenotype alone.Methods: 365 probands with GGE and 60 probands with ID-GGE were screened for GGE-associated recurrent microdeletions at 15q13.3, 15q11.2 and 16p13.11 via quantitative PCR or loss of heterozygosity. Deletions were confirmed by comparative genomic hybridization (CGH). ID-GGE probands also had genome-wide CGH.Results: ID-GGE probands showed a significantly higher rate of CNVs compared with probands with GGE alone with 17/60 (28%) of ID-GGE probands having one or more potentially causative CNV. The ID-GGE patients had a three-fold higher rate of the three GGE-associated recurrent microdeletions than probands with GGE alone (10% vs. 3%, p=0.02). They also showed a high rate (13/60, 22%) of rare CNV identified using genome-wide CGH. Conclusions: This study shows that CNVs are common in those with ID-GGE with recurrent deletions at 15q13.3, 15q11.2 and 16p13.11 particularly enriched compared with individuals with GGE or ID alone. Recurrent CNV are likely to act as risk factors for multiple phenotypes not just at the population level, but also in any given individual. Testing for CNV in ID-GGE will have a high diagnostic yield in a clinical setting and will inform genetic counseling.