INTRODUCTION
Identifying the genes that influence the risk for epilepsies is crucial
to elucidate the mechanisms that underlie seizure susceptibility (Ottman
et al., 2010). However, the complex relationship between genotype and
phenotype poses considerable difficulties when evaluating the clinical
utility of genetic testing (Ottman et al., 2010). Thus, classifying the
pathogenicity of identified variants in complex disorders with any
degree of certainty is often challenging (Cooper, Krawczak,
Polychronakos, Tyler-Smith, & Kehrer-Sawatzki, 2013). New genetic
technologies that involve massive parallel sequencing have influenced
the diagnostic practices in patients with intractable epilepsy; there
are several epilepsy gene panels that are currently commercially
available. Still, choosing a specific panel can be problematic for
clinicians (Chambers, Jansen, & Dhamija, 2016). Therefore, even using
large-scale genomic tests, such as whole-exome sequencing and
whole-genome sequencing, genetic diagnosis is restricted mainly to
single-gene disorders (Boycott, Vastone, Bulma, & MacKenzie, 2013).
Also, there has been limited success in identifying genes for complex
epilepsies, such as the genetic generalized epilepsies (GGE; Greenberg
& Stewart, 2014; Ottman et al., 2010).
The most common form of GGE is juvenile myoclonic epilepsy (JME), which
accounts for 5 to 10% of all epilepsies (Camfield, Striano, &
Camfield, 2013). The clinical presentation begins between the ages of 9
and 27 years; it is characterized by myoclonic seizures (Fisher et al.,
2017), which may be followed by generalized tonic-clonic seizures (GTCS)
and absence seizures (Leppik, 2003). One of the genes associated with
JME is EFHC1 , which encodes the EFHC1 protein, also known as
myoclonin 1 (Medina et al., 2008). Although the function of the EFHC1
protein is still poorly understood, it is known to be associated with
microtubules and, consequently, involved in the regulation of cell
division, as well as associated with the process of radial migration
during the development of the central nervous system (CNS; Conte et al.,
2009; de Nijs et al., 2009). It is believed that mutations inEFHC1 significantly impair apoptotic activity, which could
prevent the elimination of neurons with altered calcium homeostasis
during the development of the CNS, leading to JME (de Nijs et al.,
2009).
EFHC1 is currently included in 53 tests for diagnostic purposes
available in the Genetic Testing Registry
(https://www.ncbi.nlm.nih.gov/gtr; accessed in January 2020). Recently,
researchers have raised the possibility that some EFHC1 variants
might be pathogenic depending on specific genetic backgrounds in which
they are introduced (Subaran, Conte, Stewart, & Greenberg, 2015).
However, there is a lack of studies in patients with a more diverse
ethnic background; most EFHC1 variants have been found either in
Hispanics, in patients from Central America, or in Japanese individuals.
Most importantly, there have been controversies as to whether genetic
testing for EFHC1 directly impacts therapeutic decision-making,
treatment, outcome, or other aspects in the context of medical care for
patients with GGEs. On the one hand, EFHC1 has been implicated in
JME (Bailey et al., 2017). On the other hand, EFHC1 is not listed
as an epilepsy-related genetic variant with implications for clinical
management (Poduri, Sheidley, Shostak, & Ottman, 2014), and it has been
advised that prediction of epilepsy susceptibility in individuals who
harbor EFHC1 variants must be handled with caution (Subaran et
al., 2015). Therefore, it remains debatable whether EFHC1 is
clinically useful and should be included in the diagnostic gene panels
for GGEs. Thus, our study aimed to contribute to this ongoing debate.