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hypersensitivity reactions to carbamazepine across multiple ethnicities, this study estimated
that between 47 and 67 patients would need to be tested to prevent one episode of
hypersensitivity73. For phenytoin, the CYP2C9 missense variant rs1057910 (CYP2C9*3) was
significantly associated with severe cutaneous adverse reactions, an intriguing finding74.
Apart from these few findings for severe skin reactions, there are no other confirmed
pharmacogenomic findings in epilepsy currently.

For discoveries beyond severe adverse reactions, and more seizure control genomics, it may
be that the strategy will need to change focus from a drug-centred approach to a patient-
centred approach, despite the challenges that studies based on small numbers of patients raise,
both in terms of proof and regulatory requirements. There are already a few additional
examples where genetic findings of course have treatment implications. The best example is
the finding of an SCN1A mutation in an appropriate phenotype, such as Dravet syndrome,
which should usually lead to the withdrawal of sodium channel-blocking antiepileptic drugs
and consideration of valproate, benzodiazepines, and other agents including stiripentol75. In
the appropriate clinical contexts, which may be wide, other examples include: identification
of an SLC2A1 mutation leading to use of the ketogenic diet47,76-78; in PNPO or ALDH7A1
mutation, supplementation with pyridoxine or pyridoxal 5'-phosphate79; with FOLR1
mutation, use of folinic acid80. Novel therapies have been explored at some level in newer
genetic epilepsies. KCNT1-associated epilepsies were described in 2012; in 2014, reversal of
mutation-associated gain-of-function was reported in a Xenopus oocyte model using a drug
(quinidine) previously used in humans, though not one known to be an antiepileptic81.
GRIN2A mutations were reported in association with various epilepsies in late 2013; in 2014,
functional analysis of one mutation showed that the mutated protein retained sensitivity to a
known blocker (memantine) of this channel, which also reduced seizure frequency in the
single patient carrying the mutation82. Studies of genetic determinants of response to the
ketogenic diet are ongoing. The only known genetic factors predisposing to good response in
humans are mutations in SLC2A1 causing GLUT1 deficiency syndrome and some other very
rare neurometabolic conditions.

Current tools, models and problems

The landscape of epilepsy genetics is changing rapidly – which overall is likely to be to the
benefit of people with epilepsy. For the clinician, the tools available for genetic diagnosis are
aCGH, candidate gene testing, and gene panels. Array CGH applied in an appropriate clinical
setting may identify a pathogenic copy number variant in perhaps 12% of cases, as discussed
above. Candidate gene testing requires the clinician to have knowledge of the gene(s) which
may be altered to produce the observed phenotype. Some epilepsies have a very characteristic
phenotype, and gene selection may be obvious. Candidate gene testing typically uses Sanger
sequencing, to which methods such as multiplex ligation-dependent probe amplification may
be added for detecting exonic-level changes, such as exonic deletions. Dravet syndrome is
amongst the best examples: with a typical history, over 80% of cases will have a pathogenic
change in the gene SCN1A. Other genes when mutated can cause a Dravet-like phenotype,
while having an SCN1A mutation does not mean a patient has Dravet syndrome unless the
phenotype is appropriate: recent guidelines for SCN1A testing should help in these
situations83, and may be needed for other genes – another challenge for the years ahead. Gene
panels partly sidestep this issue of complex and overlapping genotype-phenotype correlation,
but have important limitations of their own, and are likely to be a step in the evolution of
genetic testing in epilepsy. Next-generation sequencing, reading much more of the available
genetic information, is already being applied in a few settings. Next-generation based panels
are in use and may be informative, but WES is still to be broadly used in epilepsy genetics.
CNVs can be difficult to pick up through WES, and aCGH, or genotyping arrays, may still
retain a role in clinical practice even when WES becomes more widely applied. Eventually,