Genetic characteristics of non-familial epilepsy

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.

Multigene Panel Testing in a Large Cohort of Adults With Epilepsy

“…These findings are consistent with previous literature that reported on the diagnostic yield in the absence of a positive family history of epilepsy and the overall high de novo rates for many of these genes. 24 , 33 These data suggest that individuals with epilepsy of unexplained cause presenting at any age and with ID/DD comorbidities, regardless of family history, often have an identifiable genetic diagnosis.…”

Case Report: Chorea-Acanthocytosis Presents as Epilepsy in a Consanguineous Family With a Nonsense Mutation of in VPS13A

“…According to the EpilepsyGene database ( http://www.wzgenomics.cn/EpilepsyGene/index.php ), ~500 genes may be associated with epilepsy, and ~2% of idiopathic epilepsy patients are thought to be monogenic (Ran et al, 2015 ). Mutations in Sodium Voltage-Gated Channel Alpha Subunit 1 ( SCN1A ), Potassium Voltage-Gated Channel Subfamily Q Member 2 ( KCNQ2 ), Cyclin Dependent Kinase Like 5 ( CDKL5 ), Protocadherin 19 ( PCDH19 ), and Proline Rich Transmembrane Protein 2 ( PRRT2 ) were the most common genetic lesions of epilepsy (Wang J. et al, 2017 ; Kang et al, 2019 ). In addition, recent studies revealed that epilepsy may be a presenting and prominent symptom of ChAc caused by VPS13A mutations (Benninger et al, 2016 ; Weber et al, 2018 ).…”

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

“…Genetic Characteristics In Drug-resistant Epilepsy Of Published Studies Table 3 provides a summary of previous studies about genetic characteristics in DRE [12][13][14][15][16][17][18][19][20][21]. Regardless of varied molecular diagnostic tool used between studies, some gene mutations were found to appear repeatedly, such as SCN1A (5.6%, n = 74/1308), followed by SCN8A (1.37%, n = 18/1308), TSC2 (1.22%, n = 16/1308), SCN2A (1.07%, n = 14/1308) and KCNQ2 (0.99%, n = 13/1308) 3).…”