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incidentally, interesting that recent research efforts in genetics are exploring the genetic
underpinnings of such phenomena, seeking shared genetic susceptibility across brain diseases
(http://www.ashg.org/2014meeting/abstracts/fulltext/f140123198.htm), and soon also across
somatic co-morbidities. More formal heritability studies, mainly based on twin cohorts, began
to define and quantify aspects of the genetic contribution to the epilepsies2,3, but have
inevitably been limited because we have not really known if the input phenotypic mixes are
biologically correct. On this background of belief in a role of genetics in causation, newer
technologies have made possible real advances not only in discovery of causes but also
discovery in other domains where genetics might have a role – such as susceptibility, specific
phenomenonological traits, pharmacogenomics and outcomes, as well as co-morbidities and
the definition of new syndromes and new categorisation of the epilepsies based on a better
understanding of causation.

Current understanding of genetics of the epilepsies

The reorganisation of the epilepsies promulgated in 2010 by the ILAE Commission on
Classification and Terminology was predicated on the belief that genetic information in the
epilepsies was informing a new understanding based on biological discovery underpinning
clinical pattern recognition4. The spate of publications in epilepsy genetics over the last few
years bears witness to this. The reorganisation was of course controversial, and it is not the
case that all the beliefs enshrined in the original reorganisation have been underpinned by
actual genetic discovery5. Nevertheless, there has been enormous progress, with discoveries
in a number of major domains: syndromic epilepsies, epileptic encephalopathies (which may
have an overlap of course with ‘syndromic’ epilepsies), progressive myoclonic epilepsies,
and a small group of generalised epilepsies and some focal epilepsies. There has also been
much more limited progress in other areas, such as treatment genomics. Most other aspects
of the epilepsies, such as outcomes and co-morbidities, have not yet been addressed. Recent
progress is reviewed here in terms of concepts, rather than in terms of every gene that has so
far been linked to epilepsy.

Discovery in epilepsy genetics, inevitably, has followed technological advances6. In the
current era, the first new genetic technology that became widely available was array
comparative genomic hybridisation (aCGH), which permits comparison of segments of a
patient’s DNA with, typically, pooled DNA from a group of controls without the same
condition, usually healthy individuals. The technique highlights segments where the number
of copies of that segment is different to that seen in controls (copy number variation), down
to a certain size resolution, usually of the order of a few hundred kilobases, but occasionally
with higher resolution. aCGH is now offered by many clinical genetics laboratories and,
because of its higher resolution and reliability, has replaced karyotyping as the first-line test
in complex epilepsy phenotypes that do not implicate an obvious candidate gene. aCGH is
indicated when the presenting epilepsy is syndromic, being associated with other features,
such as facial or somatic dysmorphism, intellectual disability, autism spectrum disorder or
multiple co-morbidities. Microdeletions and microduplications (together falling within the
category of copy number variants, CNVs) have been increasingly reported in association with
complex epilepsies7–11, and have sometimes pointed to novel candidate epilepsy genes12.
Depending on case series and criteria for inclusion, about 12% of people with complex
epilepsy might have a CNV considered relevant. In the current NHS setting, aCGH is the
first-line genetic test that should be considered in a patient with a complex phenotype for
which there is no obvious candidate gene(s). aCGH retains a place in genetics research, as
other current technologies do not always reliably pick up relevant CNVs.

Interestingly, aCGH has also proved informative for some groups of ‘genetic’ (idiopathic)
generalised epilepsies. The paper that many consider to herald the current era of genetic
discovery in epilepsy reported the first CNV associated with a common epilepsy, 15q13.3