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Review
. 2013 Oct 22;81(17):1507-14.
doi: 10.1212/WNL.0b013e3182a95829. Epub 2013 Sep 25.

Copy number variants are frequent in genetic generalized epilepsy with intellectual disability

Saul A Mullen  1 , Gemma L Carvill, Susannah Bellows, Marta A Bayly, Holger Trucks, Dennis Lal, Thoman Sander, Samuel F Berkovic, Leanne M Dibbens, Ingrid E Scheffer, Heather C Mefford
Affiliations
Review

Copy number variants are frequent in genetic generalized epilepsy with intellectual disability

Saul A Mullen et al. Neurology. .

Erratum in

  • Author response.
    Strowd R, Reynolds P. Strowd R, et al. Neurology. 2013 Dec 10;81(24):2148. doi: 10.1212/wnl.0000000000000027. Neurology. 2013. PMID: 24471170 Free PMC article. No abstract available.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

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 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.

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Figures

Figure 1
Figure 1. Pedigrees of newly identified probands with GGE and ID-GGE
Probands carrying 1 of the 3 recurrent microdeletions screened in both cohorts are included. Note proband 10 carries 2 paternally inherited deletions: 15q13.3 recurrent microdeletion and a nonrecurrent duplication at 10p15.1; the father had GGE and normal intellect. CNV = copy number variant; GGE = genetic generalized epilepsy; GTCS = generalized tonic-clonic seizure; ID = intellectual disability.
Figure 2
Figure 2. Inheritance of CNV identified by genome-wide screen in probands with ID-GGE
CNV = copy number variant; GGE = genetic generalized epilepsy; GTCS = generalized tonic-clonic seizure; ID = intellectual disability.
See this image and copyright information in PMC

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