Many forms of epilepsy have long been suspected to have a genetic background, and improvements in sequencing technology have now enabled detailed dissection of their genetic basis
The likelihood of a genetic cause of epilepsy is easily underestimated in routine clinical practice
De novo mutagenesis is increasingly being recognized as an important mechanism in some epilepsies, particularly the epileptic encephalopathies
A genetic aetiology is not synonymous with generalized epilepsy; many focal epilepsies have a known genetic cause
Genetic diagnosis can facilitate appropriate counselling and, in some patients, can also have therapeutic implications
Understanding the aetiology of epilepsy is essential both for clinical management of patients and for conducting neurobiological research that will direct future therapies. The aetiology of epilepsy was formerly regarded as unknown in about three-quarters of patients; however, massively parallel gene-sequencing studies, conducted in a framework of international collaboration, have yielded a bounty of discoveries that highlight the importance of gene mutations in the aetiology of epilepsy. These data, coupled with clinical genetic studies, suggest a new paradigm for use in the clinic: many forms of epilepsy are likely to have a genetic basis. Enquiry about a genetic cause of epilepsy is readily overlooked in the clinic for a number of understandable but remediable reasons, not least an incomplete understanding of its genetic architecture. In addition, the importance of de novo mutagenesis is often underappreciated, particularly in the epileptic encephalopathies. Other genomic surprises are worth emphasizing, such as the emerging evidence of a genetic contribution to focal epilepsies—long regarded as acquired conditions—and the complex role of copy number variation. The importance of improved understanding of the genetics of the epilepsies is confirmed by the positive outcomes, in terms of treatment selection and counselling, of receiving a genetic diagnosis.
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S.F.B. declares that he has received honoraria and/or payments for development of educational presentations from Novartis Pharmaceuticals, Sanofi-Aventis, Janssen-Cilag, and UCB Pharma, and that he is an inventor on a patent for SCN1A testing owned by Bionomics and licensed to various diagnostic companies (WO/2006/133508); he has also applied for a patent for PCDH19 testing (WO/2009/086591). R.H.T. declares no competing interests.
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Thomas, R., Berkovic, S. The hidden genetics of epilepsy—a clinically important new paradigm. Nat Rev Neurol 10, 283–292 (2014). https://doi.org/10.1038/nrneurol.2014.62
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