Hussein Yara, Weisblum-Neuman Hila, Ben Zeev Bruria, Stern Shani
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Pediatric Neurology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
Epilepsia Open. 2024 Dec;9(6):2443-2453. doi: 10.1002/epi4.13085. Epub 2024 Nov 7.
Epilepsy is a chronic neurological disorder related to various etiologies, and the prevalence of active epilepsy is estimated to be between 4 and 10 per 1000 individuals having a significant role in genetic mutations. Next-Generation Sequencing (NGS) panels are utilized for genetic testing, but a substantial proportion of the results remain uncertain and are not considered directly causative of epilepsy. This study aimed to reevaluate pediatric patients diagnosed with epilepsy who underwent genetic investigation using NGS panels, focusing on inconclusive variant findings or multiple variants of uncertain significance (VUSs).
A subgroup of pediatric patients aged 0-25 years, diagnosed with epilepsy, who underwent genetic investigation with an NGS epilepsy panel at the Child Neurology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, between 2018 and 2022 through Invitae, was reevaluated. Patients with inconclusive variant findings or multiple VUSs in their test results were included. Genetic data were analyzed to identify potentially pathogenic variants and frequent genetic combinations.
Two unrelated potentially pathogenic variants were identified in the SCN9A and QARS1 genes. A frequent genetic combination, RANBP2&RYR3, was also observed among other combinations. The RANBP2 gene consistently co-occurred with RYR3 variants in uncertain results, suggesting potential pathogenicity. Analysis of unaffected parents' data revealed certain combinations inherited from different parents, suggesting specific gene combinations as possible risk factors for the disease.
This study highlights the importance of reevaluating genetic data from pediatric epilepsy patients with inconclusive variant findings or multiple VUSs. Identification of potentially pathogenic variants and frequent genetic combinations, such as RANBP2&RYR3, could aid in understanding the genetic basis of epilepsy and identifying potential hotspots.
We have performed a retrospective analysis on a subpopulation of pediatric patients diagnosed with epilepsy. We found that specific genetic variants were repeatable, indicating their potential pathogenicity to the disease.
癫痫是一种与多种病因相关的慢性神经系统疾病，活动性癫痫的患病率估计为每1000人中有4至10人，基因突变在其中起重要作用。下一代测序（NGS）面板用于基因检测，但相当一部分结果仍不确定，不被认为是癫痫的直接病因。本研究旨在重新评估使用NGS面板进行基因检测的癫痫患儿，重点关注不确定的变异结果或多个意义未明的变异（VUS）。
对2018年至2022年期间在舍巴医疗中心爱德蒙和莉莉·萨夫拉儿童医院儿童神经科通过Invitae使用NGS癫痫面板进行基因检测的0至25岁癫痫患儿亚组进行重新评估。纳入检测结果有不确定变异结果或多个VUS的患者。分析基因数据以识别潜在的致病变异和常见的基因组合。
在SCN9A和QARS1基因中鉴定出两个不相关的潜在致病变异。在其他组合中还观察到一种常见的基因组合RANBP2&RYR3。在不确定结果中，RANBP2基因始终与RYR3变异共同出现，提示潜在致病性。对未受影响父母的数据进行分析发现，某些组合是从不同父母遗传而来，表明特定的基因组合可能是该疾病的危险因素。
本研究强调了重新评估具有不确定变异结果或多个VUS的癫痫患儿基因数据的重要性。识别潜在的致病变异和常见的基因组合，如RANBP2&RYR3，有助于理解癫痫的遗传基础并识别潜在热点。
我们对诊断为癫痫的儿科患者亚群进行了回顾性分析。我们发现特定的基因变异具有重复性，表明它们对该疾病具有潜在致病性。
