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.