Genetically Complex Epilepsies, Copy Number Variants and Syndrome Constellations

Overview

Journal Genome Med

Publisher Biomed Central

Specialty Genetics

Date 2010 Oct 7

PMID 20923578

Citations 14

Authors

Heather C Mefford

John C Mulley

Affiliations

Soon will be listed here.

Abstract

Epilepsy is one of the most common neurological disorders, with a prevalence of 1% and lifetime incidence of 3%. There are numerous epilepsy syndromes, most of which are considered to be genetic epilepsies. Despite the discovery of more than 20 genes for epilepsy to date, much of the genetic contribution to epilepsy is not yet known. Copy number variants have been established as an important source of mutation in other complex brain disorders, including intellectual disability, autism and schizophrenia. Recent advances in technology now facilitate genome-wide searches for copy number variants and are beginning to be applied to epilepsy. Here, we discuss what is currently known about the contribution of copy number variants to epilepsy, and how that knowledge is redefining classification of clinical and genetic syndromes.

Citing Articles

Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.

Gall K, Izzo E, Seppala E, Alakurtti K, Koskinen L, Saarinen I PLoS One. 2021; 16(9):e0255933.

PMID: 34469436 PMC: 8409681. DOI: 10.1371/journal.pone.0255933.

Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects.

Niestroj L, Perez-Palma E, Howrigan D, Zhou Y, Cheng F, Saarentaus E Brain. 2020; 143(7):2106-2118.

PMID: 32568404 PMC: 7364765. DOI: 10.1093/brain/awaa171.

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy.

Rudolf G, Lesca G, Mehrjouy M, Labalme A, Salmi M, Bache I Eur J Hum Genet. 2016; 24(12):1761-1770.

PMID: 27352968 PMC: 5117930. DOI: 10.1038/ejhg.2016.80.

Copy number variants in the population: unselected does not mean unaffected.

Mefford H Epilepsy Curr. 2016; 16(2):91-3.

PMID: 27073338 PMC: 4822738. DOI: 10.5698/1535-7511-16.2.91.

Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.

Lal D, Ruppert A, Trucks H, Schulz H, de Kovel C, Kasteleijn-Nolst Trenite D PLoS Genet. 2015; 11(5):e1005226.

PMID: 25950944 PMC: 4423931. DOI: 10.1371/journal.pgen.1005226.

References

Suls A, Velizarova R, Yordanova I, Deprez L, Van Dyck T, Wauters J . Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene. Neurology. 2010; 75(1):72-6. DOI: 10.1212/WNL.0b013e3181e62088. View

Reid C, Berkovic S, Petrou S . Mechanisms of human inherited epilepsies. Prog Neurobiol. 2008; 87(1):41-57. DOI: 10.1016/j.pneurobio.2008.09.016. View

Feng H, Kang J, Song L, Dibbens L, Mulley J, Macdonald R . Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors. J Neurosci. 2006; 26(5):1499-506. PMC: 6675478. DOI: 10.1523/JNEUROSCI.2913-05.2006. View

Hauser W, Annegers J, Rocca W . Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc. 1996; 71(6):576-86. DOI: 10.4065/71.6.576. View

Depienne C, Trouillard O, Saint-Martin C, Gourfinkel-An I, Bouteiller D, Carpentier W . Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2008; 46(3):183-91. DOI: 10.1136/jmg.2008.062323. View

Berg A, Berkovic S, Brodie M, Buchhalter J, Cross J, van Emde Boas W . Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010; 51(4):676-85. DOI: 10.1111/j.1528-1167.2010.02522.x. View

Tan N, Mulley J, Berkovic S . Genetic association studies in epilepsy: "the truth is out there". Epilepsia. 2004; 45(11):1429-42. DOI: 10.1111/j.0013-9580.2004.22904.x. View

Shaikh T, Gai X, Perin J, Glessner J, Xie H, Murphy K . High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res. 2009; 19(9):1682-90. PMC: 2752118. DOI: 10.1101/gr.083501.108. View

Zody M, Garber M, Sharpe T, Young S, Rowen L, ONeill K . Analysis of the DNA sequence and duplication history of human chromosome 15. Nature. 2006; 440(7084):671-5. DOI: 10.1038/nature04601. View

10.

Elmslie F, Rees M, Williamson M, Kerr M, Kjeldsen M, Pang K . Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet. 1997; 6(8):1329-34. DOI: 10.1093/hmg/6.8.1329. View

11.

Mefford H . Genotype to phenotype-discovery and characterization of novel genomic disorders in a "genotype-first" era. Genet Med. 2009; 11(12):836-42. DOI: 10.1097/GIM.0b013e3181c175d2. View

12.

Price A, Kryukov G, de Bakker P, Purcell S, Staples J, Wei L . Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet. 2010; 86(6):832-8. PMC: 3032073. DOI: 10.1016/j.ajhg.2010.04.005. View

13.

Helbig I, Mefford H, Sharp A, Guipponi M, Fichera M, Franke A . 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009; 41(2):160-2. PMC: 3026630. DOI: 10.1038/ng.292. View

14.

Mullen S, Suls A, De Jonghe P, Berkovic S, Scheffer I . Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology. 2010; 75(5):432-40. DOI: 10.1212/WNL.0b013e3181eb58b4. View

15.

Sharp A . Emerging themes and new challenges in defining the role of structural variation in human disease. Hum Mutat. 2008; 30(2):135-44. DOI: 10.1002/humu.20843. View

16.

Conrad D, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y . Origins and functional impact of copy number variation in the human genome. Nature. 2009; 464(7289):704-12. PMC: 3330748. DOI: 10.1038/nature08516. View

17.

Taske N, Williamson M, Makoff A, Bate L, Curtis D, Kerr M . Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14. Epilepsy Res. 2002; 49(2):157-72. DOI: 10.1016/s0920-1211(02)00027-x. View

18.

Mardis E . The impact of next-generation sequencing technology on genetics. Trends Genet. 2008; 24(3):133-41. DOI: 10.1016/j.tig.2007.12.007. View

19.

Mei D, Marini C, Novara F, Bernardina B, Granata T, Fontana E . Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy. Epilepsia. 2009; 51(4):647-54. DOI: 10.1111/j.1528-1167.2009.02308.x. View

20.

Mulley J, Nelson P, Guerrero S, Dibbens L, Iona X, McMahon J . A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A. Neurology. 2006; 67(6):1094-5. DOI: 10.1212/01.wnl.0000237322.04338.2b. View