Copy number variants are frequent in genetic generalized epilepsy with intellectual disability
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The medical literature indicates that the 15q11.2 BP1-BP2 microdeletion may be a risk factor for epilepsy.
“The medical literature surrounding this microdeletion syndrome and seizures indicate that this chromosomal anomaly may be a risk factor for epilepsy [29,41,42,43].”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [43]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Microduplications of 16p11.2 are associated with schizophrenia
Wellcome Trust Case Control Consortium, McCarthy, S. E., Makarov, V., Kirov, G., Addington, A. M., McClellan, J., Yoon, S., Perkins, D. O., Dickel, D. E., Kusenda, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.474 · Cited by 711 · see citing works
Population analysis of large copy number variants and hotspots of human genetic disease
Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.12.014 · Cited by 591 · see citing works
Self-citationA recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures.
Sharp, A. J., Mefford, H. C., Li, K., Baker, C., Skinner, C., Stevenson, R. E., Schroer, R. J., Novara, F., De Gregori, M., Ciccone, R., et al. (2008) · Nature Genetics · doi:10.1038/ng.93 · Cited by 582 · see citing works
Self-citationShinawi, M., Liu, P., Kang, S.-H. L., Shen, J., Belmont, J. W., Scott, D. A., Probst, F. J., Craigen, W. J., Graham, B. H., Pursley, A., et al. (2010) · Journal of Medical Genetics · doi:10.1136/jmg.2009.073015 · Cited by 580 · see citing works
15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
Helbig, I., Mefford, H. C., Sharp, A. J., Guipponi, M., Fichera, M., Franke, A., Muhle, H., de Kovel, C., Baker, C., von Spiczak, S., et al. (2009) · Nature Genetics · doi:10.1038/ng.292 · Cited by 551 · see citing works
Self-citationMefford, H. C., Muhle, H., Ostertag, P., von Spiczak, S., Buysse, K., Baker, C., Franke, A., Malafosse, A., Genton, P., Thomas, P., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000962 · Cited by 474 · see citing works
Self-citationRecurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
de Kovel, C. G. F., Trucks, H., Helbig, I., Mefford, H. C., Baker, C., Leu, C., Kluck, C., Muhle, H., von Spiczak, S., Ostertag, P., et al. (2010) · Brain · doi:10.1093/brain/awp262 · Cited by 445 · see citing works
Self-citationA 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
Zufferey, F., Sherr, E. H., Beckmann, N. D., Hanson, E., Maillard, A. M., Hippolyte, L., Macé, A., Ferrari, C., Kutalik, Z., Andrieux, J., et al. (2012) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2012-101203 · Cited by 326 · see citing works
Flagged first, then by citations
Research works printed but not linked: 20
- Sharp AJ. Emerging themes and new challenges in defin- ing the role of structural variation in human disease. Hum Mutat 2009;30:135-144.
- Dibbens LM, Mullen S, Helbig I, et al. Familial and spo- radic 15q13.3 microdeletions in idiopathic generalized epi- lepsy: precedent for disorders with complex inheritance. Hum Mol Genet 2009;18:3626-3631.
- Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminol- ogy and concepts for organization of seizures and epilep- sies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-685.
- van Bon BW, Mefford HC, Menten B, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009;46:511-523.
- Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008;455:232-236.
- Need AC, Ge D, Weale ME, et al. A genome-wide inves- tigation of SNPs and CNVs in schizophrenia. PLoS Genet 2009;5:e1000373.
- Sharp AJ, Hansen S, Selzer RR, et al. Discovery of previ- ously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006;38: 1038-1042.
- Pagnamenta AT, Wing K, Akha ES, et al. A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet 2009;17:687-692.
- Miller DT, Shen Y, Weiss LA, et al. Microdeletion/dupli- cation at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 2009;46:242-248.
- Muhle H, Mefford HC, Obermeier T, et al. Absence seizures with intellectual disability as a phenotype of the 15q13.3 microdeletion syndrome. Epilepsia 2011;52: e194-e198.
- Reutens DC, Howell RA, Gebert KE, Berkovic SF. Vali- dation of a questionnaire for clinical seizure diagnosis. Epilepsia 1992;33:1065-1071.
- Grozeva D, Conrad DF, Barnes CP, et al. Independent estimation of the frequency of rare CNVs in the UK pop- ulation confirms their role in schizophrenia. Schizophr Res 2012;135:1-7.
- Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopa- thies. Ann Neurol 2011;70:974-985.
- Shaikh TH, Gai X, Perin JC, et al. High-resolution map- ping and analysis of copy number variations in the human genome: a data resource for clinical and research applica- tions. Genome Res 2009;19:1682-1690.
- Hannes FD, Sharp AJ, Mefford HC, et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplica- tion may be a rare benign variant. J Med Genet 2009;46: 223-232.
- International Schizophrenia Consortium. Rare chromo- somal deletions and duplications increase risk of schizo- phrenia. Nature 2008;455:237-241.
- Bachmann-Gagescu R, Mefford HC, Cowan C, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med 2010;12:641-647.
- Walters RG, Jacquemont S, Valsesia A, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010;463:671-675.
- Veredice C, Bianco F, Contaldo I, et al. Early onset myo- clonic epilepsy and 15q26 microdeletion: observation of the first case. Epilepsia 2009;50:1810-1815.
- Carvill GL, Heavin SB, Yendle SC, et al. Targeted rese- quencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013;45: 825-830.
Cited by
Sorted by citations
Hirsch, E., French, J., Scheffer, I. E., Bogacz, A., Alsaadi, T., Sperling, M. R., Abdulla, F., Zuberi, S. M., Trinka, E., Specchio, N., et al. (2022) · Epilepsia · doi:10.1111/epi.17236 · Cited by 502 · see citing works
Self-citationThe 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review
Cox, D., & Butler, M. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16024068 · Cited by 243 · see citing works
Yoon, K.-J., Nguyen, H. N., Ursini, G., Zhang, F., Kim, N.-S., Wen, Z., Makri, G., Nauen, D., Shin, J. H., Park, Y., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.05.003 · Cited by 240 · see citing works
Steinman, K. J., Spence, S. J., Ramocki, M. B., Proud, M. B., Kessler, S. K., Marco, E. J., Green Snyder, L., D'Angelo, D., Chen, Q., Chung, W. K., et al. (2016) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.37820 · Cited by 218 · see citing works
Scheffer, I. E., & Liao, J. (2020) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2019.12.023 · Cited by 180 · see citing works
Self-citation<i>CHD2</i> myoclonic encephalopathy is frequently associated with self-induced seizures
Thomas, R. H., Zhang, L. M., Carvill, G. L., Archer, J. S., Heavin, S. B., Mandelstam, S. A., Craiu, D., Berkovic, S. F., Gill, D. S., Mefford, H. C., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000001305 · Cited by 100 · see citing works
Self-citationJønch, A. E., Douard, E., Moreau, C., Van Dijck, A., Passeggeri, M., Kooy, F., Puechberty, J., Campbell, C., Sanlaville, D., Lefroy, H., et al. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2018-105879 · Cited by 75 · see citing works
Extending the phenotypic spectrum of <i><scp>RBFOX</scp>1</i> deletions: Sporadic focal epilepsy
Lal, D., Pernhorst, K., Klein, K. M., Reif, P., Tozzi, R., Toliat, M. R., Winterer, G., Neubauer, B., Nürnberg, P., Rosenow, F., et al. (2015) · Epilepsia · doi:10.1111/epi.13076 · Cited by 40 · see citing works
- Authors
- Mullen, S. A., Carvill, G. L., Bellows, S., Bayly, M. A., Berkovic, S. F., Dibbens, L. M., Scheffer, I. E., & Mefford, H. C.
- Affiliations
- Royal Children's Hospital (AU)
- ORCID
- Venue
- Neurology
- Published
- 2013-10-22
- Volume
- 81
- Issue
- 17
- Pages
- 1507-1514
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3888172
- OpenAlex
- W2091134548
- Cited by
- 188
- References
- 8
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 18 · 2020: 16 · 2019: 13 · 2018: 44 · 2017: 11 · 2016: 15 · 2015: 23 · 2014: 11
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Update notices
- correction (2013-12-10)
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- U.S. Department of Defense
- Simons Foundation
- GlaxoSmithKline
- Sanofi
- Wellcome Trust (1007607.01)
- Jack Brockhoff Foundation
- Simons Foundation Autism Research Initiative
- University of Melbourne
- Epilepsy Society
- Shepherd Foundation
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- Health Research Council of New Zealand
- National Institute of Neurological Disorders and Stroke (R01NS069605)
- UCB Pharma
- Cilag
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- copy number variation, idiopathic generalized epilepsy, intellectual disability, 15q13.3, 15q11.2, neurodevelopmental disorders, genetic counseling, diagnostic yield
- MeSH terms
- Adolescent, Adult, Aged, Child, Chromosome Aberrations, Chromosome Deletion, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 16, Epilepsy, Generalized, Female, Genetic Testing, Humans, Male, Intellectual Disability, Middle Aged, Phenotype, Rubinstein-Taybi Syndrome, Seizures, Cohort Studies, Comorbidity, Case-Control Studies, Chromosome Disorders, Young Adult, DNA Copy Number Variations
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
