Abstract
The clinical utility of genetic testing for epilepsy has been enhanced with the advancement of next-generation sequencing (NGS) technology along with the rapid updating of publicly available databases. The aim of this study was to evaluate the diagnostic yield of NGS and assess the value of reinterpreting genetic test results in children and adults with epilepsy. We performed genetic testing on 200 patients, including 82 children and 118 adults. The results were classified into three categories: positive, inconclusive, or negative. The reinterpretation of inconclusive results was conducted in April 2020. Overall, we identified disease-causing variants in 12% of the patients in the original analysis, and 14.5% at reinterpretation. The diagnostic yield for adults with epilepsy was similar to that for children (11 vs. 19.5%, p = 0.145). After reinterpretation, 9 of the 86 patients who initially had inconclusive results obtained a clinically significant change in diagnosis. Among these nine revised cases, five obtained positive diagnoses, representing a diagnosis rate of 5.8% (5/86). Manual searches for additional evidence of pathogenicity for candidate variants and updated patient clinical information were the main reasons for diagnostic reclassification. This study emphasizes the diagnostic potential of combining NGS and reinterpretation of inconclusive genetic test reports in children and adults with epilepsy.
Highlights
Epilepsy is a common and highly heterogeneous neurological disease, with an estimated prevalence of 6 per 1,000 in the general population (Fiest et al, 2017)
The phenotypes associated with epilepsy syndromes are often variable and unspecific, involving several genes, next-generation sequencing (NGS) and Reinterpretation in Epilepsy while specific genetic variants are frequently associated with a wide phenotypic spectrum (Zhu et al, 2014)
Generalized epilepsy was reported in 101 cases (50.5%), focal epilepsy in 49 patients (24.5%), combined generalized and focal epilepsy in 41 patients (20.5%), while unknown epilepsy type was reported for 9 patients (4.5%)
Summary
Epilepsy is a common and highly heterogeneous neurological disease, with an estimated prevalence of 6 per 1,000 in the general population (Fiest et al, 2017). It is thought that more than 70% of epilepsy cases have a genetic basis in both children and adults (Myers et al, 2019; Scala et al, 2020). The phenotypes associated with epilepsy syndromes are often variable and unspecific, involving several genes, NGS and Reinterpretation in Epilepsy while specific genetic variants are frequently associated with a wide phenotypic spectrum (Zhu et al, 2014). This considerable heterogeneity makes it challenging to precisely identify the underlying genetic cause of most epilepsies
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