Abstract
BackgroundKnowledge of the genetic etiology of epilepsy can provide essential prognostic information and influence decisions regarding treatment and management, leading us into the era of precision medicine. However, the genetic basis underlying epileptogenesis or epilepsy pharmacoresistance is not well-understood, particularly in non-familial epilepsies with heterogeneous phenotypes that last until or start in adulthood.MethodsWe sought to determine the contribution of known epilepsy-associated genes (EAGs) to the causation of non-familial epilepsies with heterogeneous phenotypes and to the genetic basis underlying epilepsy pharmacoresistance. We performed a multi-center study for whole exome sequencing-based screening of 178 selected EAGs in 243 non-familial adult patients with primarily focal epilepsy (122 drug-resistant and 121 drug-responsive epilepsies). The pathogenicity of each variant was assessed through a customized stringent filtering process and classified according to the American College of Medical Genetics and Genomics guidelines.ResultsPossible causal genetic variants of epilepsy were uncovered in 13.2% of non-familial patients with primarily focal epilepsy. The diagnostic yield according to the seizure onset age was 25% (2/8) in the neonatal and infantile period, 11.1% (14/126) in childhood and 14.7% (16/109) in adulthood. The higher diagnostic yields were from ion channel-related genes and mTOR pathway-related genes, which does not significantly differ from the results of previous studies on familial or early-onset epilepsies. These potentially pathogenic variants, which were identified in genes that have been mainly associated with early-onset epilepsies with severe phenotypes, were also linked to epilepsies that start in or last until adulthood in this study. This finding suggested the presence of one or more disease-modifying factors that regulate the onset time or severity of epileptogenesis. The target hypothesis of epilepsy pharmacoresistance was not verified in our study. Instead, neurodevelopment-associated epilepsy genes, such as TSC2 or RELN, or structural brain lesions were more strongly associated with epilepsy pharmacoresistance.ConclusionsWe revealed a fraction of possible causal genetic variants of non-familial epilepsies in which genetic testing is usually overlooked. In this study, we highlight the importance of earlier identification of the genetic etiology of non-familial epilepsies, which leads us to the best treatment options in terms of precision medicine and to future neurobiological research for novel drug development. This should be considered a justification for physicians determining the hidden genetics of non-familial epilepsies that last until or start in adulthood.
Highlights
Epilepsy is one of the most common neurological conditions affecting approximately eight of every 1,000 individuals worldwide (Fiest et al, 2017)
Neurodevelopment-associated epilepsy genes, such as TSC2 or related genes (RELN), or structural brain lesions were more strongly associated with epilepsy pharmacoresistance
Unlike neonatal- and childhood-onset epilepsy, in which both availability of genetic testing and the actionability of test results are higher (Møller et al, 2016), enquiry into genetic causes of epilepsy has been overlooked in adult patients with epilepsy (APEs) for a number of reasons (Thomas & Berkovic, 2014): underappreciation of the role of genetic factors in certain epilepsies such as adult-onset focal epilepsy, an inexact causal attribution such as mistakenly ascribing a developmental epileptic encephalopathy (DEE) to birth trauma and, not least, unknown family history resulting from the absence of the oldest living relative who tends to be the most accurate custodian of family history or excessive social stigma leading to non-disclosure of seizures in the patient’s older relatives
Summary
Epilepsy is one of the most common neurological conditions affecting approximately eight of every 1,000 individuals worldwide (Fiest et al, 2017). Hundreds of genes have already been associated with epilepsy to date (Wang et al, 2017), and have been incorporated into commercial clinical tests with comprehensive gene panels for the rapid identification of causative genetic mutations of many forms of epilepsy (Møller et al, 2016; Hildebrand et al, 2016; Dunn et al, 2018) This is highly important, because knowledge of the genetic etiology can provide essential prognostic information and influence decisions regarding treatment and management, leading us into the era of precision medicine (Milligan et al, 2014; Pierson et al, 2014; Lindy et al, 2018). These potentially pathogenic variants, which were identified in genes that have been mainly associated with early-onset epilepsies with severe phenotypes, were linked to epilepsies that start in or last until adulthood in this
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