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(ESES)/continuous spike and wave during slow-wave sleep syndrome (CSWSS), and typical
and atypical rolandic epilepsies39-41.

The progressive myoclonic epilepsies (PMEs) were amongst the most successfully studied
from a genetic perspective even before WES. Genetic discovery has proved demonstrably
valuable in understanding disease biology, especially for example for Lafora disease and
Unverricht-Lundborg disease42, though breakthroughs in treatment options are still awaited.
There have been further discoveries in the PMEs, some of which could be considered
surprising. ‘North Sea’ progressive myoclonus epilepsy has been found to be due to
homozygous mutation in GOSR2, and has a distinctive phenotype, with all patients having a
progressive and relentless course, and all developing scoliosis by adolescence, sometimes
with other skeletal findings43. A systematic examination of 84 unsolved PME cases using
WES as the discovery tool found causal mutation in 31%44. Most interestingly, a recurrent de
novo mutation was found in an ion channel gene (KCNC1) and identified as a new major
cause for PME, with eleven unrelated exome-sequenced (13%) and two affected individuals
in a secondary cohort (7%) carrying this mutation. KCNC1 encodes a subunit of voltage-
gated potassium ion channels, which have major influence on high-frequency neuronal firing.
The detected recurrent mutation causes a dominant-negative loss-of-function effect. Other
cases within this cohort that had not been explained were found to have pathogenic mutations
in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and
SERPINI1), while unsuspected mutations were identified in other genes that had previously
not been linked to epilepsy and/or PME, including the TBC1D24 gene. It is fascinating that
while WES is increasingly identifying genes that do not encode ion channels in other
epilepsies, in the PMEs which have not traditionally been considered channelopathies, WES
has revealed the involvement of an ion channel, and other genes for which PME was not
considered part of the phenotypic spectrum before. This discovery further compromises the
idea of gene panels as currently conceptualised.

Despite the clear indications from both epidemiological, and early molecular, genetic studies
of probable significant genetic contribution to the genetic generalised epilepsies, such as
juvenile myoclonic epilepsy, juvenile absence epilepsy and childhood absence epilepsy, there
are still very few genes definitively linked to these phenotypes. In early-onset absence
epilepsy, mutations in the SLC2A1 gene, encoding a cerebral glucose transporter and causing
GLUT1 deficiency, were reported in one study in about 10% of cases45. Subsequently, a
review of seven studies identified SLC2A1 mutation in 2.4% (29) of 1110 patients with
generalised epilepsies overall, with a higher rate (5.6%) among 303 patients with early-onset
absence epilepsy46. Clues to a possible SLC2A1 mutation were the additional presence of
abnormal movements or a family history of seizures, abnormal movements, or both. As
GLUT1 deficiency can be treated with the ketogenic diet, it is important to identify its
presence. No other glucose or lactate transporters have been implicated in early-onset absence
epilepsy47, and no other generalised epilepsies have been shown to be due to SLC2A1
mutation48. Mutations or deletions in a variety of genes have been identified in genetic
epilepsy with febrile seizures plus (previously known as generalised epilepsy with febrile
seizures plus, both GEFS+), including SCN1A, PCDH19, SCN1B, SCN2A, and GABRG249–
51. But most cases of all of these epilepsy types, that is the vast majority of genetic generalised
epilepsies, remain genetically unexplained, even with systematic WES. It has also recently
been shown that the involvement of EFHC1 in juvenile myoclonic epilepsy needs to be
reconsidered52, with a number of lines of enquiry raising doubts about the pathogenicity of
detected mutations, as nicely outlined in a sobering reminder that the standards for declaring
causality must be robust and that supporting evidence should be multidimensional53. The
genetic generalised epilepsies remain a conundrum, with ‘genetic’ in the currently-
recommended name, but little ‘genetic’ in terms of actual genes.