Copy number variants are frequent in genetic generalized epilepsy with intellectual disability.
We examined whether copy number variants (CNVs) were more common in those with a combination of intellectual disability (ID) and genetic generalized epilepsy (GGE) than in those with either phenotype alone via a case-control study.



CNVs contribute to the genetics of multiple neurodevelopmental disorders with complex inheritance, including GGE and ID. Three hundred fifty-nine 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.



ID-GGE probands showed a significantly higher rate of CNVs compared with probands with GGE alone, with 17 of 60 (28%) ID-GGE probands having one or more potentially causative CNVs. The patients with ID-GGE had a 3-fold-higher rate of the 3 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 CNVs identified using genome-wide CGH.



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 CNVs are likely to act as risk factors for multiple phenotypes not just at the population level, but also in any given individual. Testing for CNVs in ID-GGE will have a high diagnostic yield in a clinical setting and will inform genetic counseling.
From the Florey Institute of Neuroscience and Mental Health (S.A.M., I.E.S.), Epilepsy Research Centre, Department of Medicine, Austin and Northern Health (S.B., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Department of Pediatrics (G.L.C., H.C.M.), Division of Genetic Medicine, University of Washington, Seattle; and Epilepsy Research Program, School of Pharmacy and Medical Sciences (M.A.B., L.M.D.), and Sansom Institute for Health Research (M.A.B., L.M.D.), University of South Australia, Adelaide.
Saul A
SA
Mullen
Gemma L
GL
Carvill
Susannah
S
Bellows
Marta A
MA
Bayly
Holger
H
Trucks
Dennis
D
Lal
Thoman
T
Sander
Samuel F
SF
Berkovic
Leanne M
LM
Dibbens
Ingrid E
IE
Scheffer
Heather C
HC
Mefford
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D015331:Cohort Studies; D015897:Comorbidity; D056915:DNA Copy Number Variations / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012415:Rubinstein-Taybi Syndrome / Q000235:genetics; D012640:Seizures / Q000235:genetics; D055815:Young Adult