Rzadkie warianty genetyczne u dorosłych z epilepsją skroniową leczoną chirurgicznie: badanie sekwencjonowania egzomu

OBJECTIVE: To determine the frequency of monogenic variants and pathogenic copy number variants (CNVs) in adults with surgically treated temporal lobe epilepsy (TLE). METHODS: We performed exome sequencing (ES), including CNV analysis, in 45 adults with TLE who had previously undergone epilepsy surgery. A diagnostic exome-wide analysis was conducted to identify (likely) pathogenic variants related to epilepsy. In an exploratory approach, we screened a curated list of 45 common epilepsy genes for rare deleterious variants based on AlphaMissense and REVEL in silico predictions. RESULTS: No highly penetrant monogenic variants were identified in this cohort. Pathogenic CNVs were detected in two individuals, corresponding to 4.4% of the cohort: a 16p13.11 deletion in a surgery responder and a 22q11.2 duplication in a surgery nonresponder. Both CNVs are characterized by reduced penetrance and broad phenotypic variability. Moreover, we identified two predicted deleterious missense variants in the epilepsy-associated genes KCNT1 and SLC2A1, both of which were detected in surgery nonresponders. In silico analyses, including structural evidence, suggested a potential impact on protein function; however, their clinical significance remains uncertain. SIGNIFICANCE: Monogenic causes are exceedingly rare in adults with surgically treated TLE, whereas CNVs may contribute to disease susceptibility in a small subset of patients. Our findings are consistent with previous reports indicating a low diagnostic yield of presurgical genetic testing and further support a predominantly polygenic architecture of TLE. PLAIN LANGUAGE SUMMARY: Temporal lobe epilepsy (TLE) is a common type of epilepsy in adults, and some patients undergo surgery when medications fail. It is unclear whether genetic testing can help predict surgical success. In this study, we used comprehensive genetic testing in 45 adult TLE patients who had undergone epilepsy surgery. We did not find single-gene causes of epilepsy. Two patients had structural genetic changes, which increase epilepsy risk but show variable effects. We also identified a few rare variants in epilepsy-related genes, but their clinical relevance remains uncertain. Overall, our results suggest that single-gene causes are rare in adults with TLE. Genetic testing may therefore have a low diagnostic rate in this population.