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it seems likely that whole genome sequencing (WGS), will become a standard clinical tool,
as it can significantly increase yield.

For clinicians, it is important to consider genetic testing as part of the armamentarium that
can be used to better understand epilepsy in an individual. Genetic testing should be
considered alongside other investigations such as MRI and EEG. WES and WGS are where
MRI was 20 years ago – available only in specialist centres if at all, and still presenting
important challenges in analysis and interpretation. As with MRI, it seems likely that WES
or WGS will become part of the clinical investigation of many more people with epilepsy, to
inform understanding of causation, prognosis, treatment, and co-morbidities. The model for
genetics should change from its use in occasional cases, to its integration into routine practice
as a source of important individual information that alters management. While the current
focus is on the genetic code, other aspects of genetic information, such as the control of gene
expression through epigenetic regulation, the role of a variety of RNA species and
translational modifications, may also eventually prove important, though the need for organ-
specific testing makes these avenues hard to explore, at least currently. Moreover, even
current and imminent technologies that may advance knowledge will present hurdles. Such
issues range from the conceptual, even for familial epilepsies where the condition may be
Mendelian, but not necessarily monogenic, to practical considerations such as how the mass
of data emerging from genetic testing will be stored, who will have control over its use, how
such truly big data will be analysed, how results will be interpreted in the context of the
individuals rather than populations, how the relevance of complex gene networks can be
judged in an inaccessible organ part way through the natural history of an individual’s
epilepsy, and how all this can be managed in an appropriate and just ethical and social
environment. At the very least, it seems likely that to realise the full benefits from genomic
data in clinical practice will require a multidisciplinary team and changed models of
management, which will allow, albeit carefully regulated, individual-level drug repurposing.
Among the best outcomes, perhaps we can also hope that epilepsy genomics will also bring
better care for the vast majority of people with epilepsy across the world who today do not
have access to any care at all. The genome is, after all, our shared heritage.

References

1. GOWERS W. Epilepsy and Other Chronic Convulsive Disorders. Churchill, London, 1881.
2. Kjeldsen MJ, Kyvik KO, Christensen K, Friis ML. Genetic and environmental factors in epilepsy: a population-

based study of 11900 Danish twin pairs. Epilepsy Res 2001;44(2-3):167-78.
3. Vadlamudi L, Milne RL, Lawrence K et al. Genetics of epilepsy: The testimony of twins in the molecular era.

Neurology 2014;83(12):1042-8.
4. Berg AT, Berkovic SF, Brodie MJ et al. 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.
5. Panayiotopoulos CP. The new ILAE report on terminology and concepts for the organization of epilepsies: critical
review and contribution. Epilepsia 2012;53(3):399-404.
6. Scheffer IE, Mefford HC. Epilepsy: Beyond the single nucleotide variant in epilepsy genetics. Nat Rev Neurol
2014;10(9):490-1.
7. Mefford HC, Yendle SC, Hsu C et al. Rare copy number variants are an important cause of epileptic
encephalopathies. Ann Neurol 2011;70(6):974-85.
8. Galizia EC, Srikantha M, Palmer R et al. Array comparative genomic hybridization: results from an adult
population with drug-resistant epilepsy and co-morbidities. Eur J Med Genet 2012;55(5):342-8.
9. Striano P, Coppola A, Paravidino R et al. Clinical significance of rare copy number variations in epilepsy: a case-
control survey using microarray-based comparative genomic hybridization. Arch Neurol 2012;69(3):322-30.
10. Olson H, Shen Y, Avallone J et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol
2014;75(6):943-58.
11. Helbig I, Swinkels ME, Aten E Structural genomic variation in childhood epilepsies with complex phenotypes.
Eur J Hum Genet 2014;22(7):896-901.
12. Saitsu H, Kato M, Mizuguchi T et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early
infantile epileptic encephalopathy. Nat Genet 2008;40(6):782-8.
13. Helbig I, Mefford HC, Sharp AJ et al. 15q13.3microdeletions increase risk of idiopathic generalized epilepsy. Nat
Genet 2009;41(2):160-2.
14. Lowther C, Costain G, Stavropoulos DJ et al. Delineating the 15q13.3 microdeletion phenotype: a case series and
comprehensive review of the literature. Genet Med 2015;17(2):149-57.