Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042, Belgrade, Serbia.
Institute for Mother and Child Healthcare of Serbia, "Dr Vukan Cupic", Belgrade, Serbia.
Mol Diagn Ther. 2024 Sep;28(5):645-663. doi: 10.1007/s40291-024-00720-2. Epub 2024 Jul 14.
Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies. The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets.
In our study, 55 children with epilepsy of unknown etiology were analyzed by combining clinical-exome and whole-exome sequencing. Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction.
The molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in five unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes such as ASH1L, CSNK2B, RHOBTB2, and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, we identified variants in ALDH7A1, KCNQ2, PNPO, SCN1A, and SCN2A resulting in gene-directed therapy decisions for 11 children from our study, including four children who all carried novel SCN1A genetic variants.
Described novel variants will contribute to a better understanding of the European genetic landscape, while insights into the genotype-phenotype correlation will contribute to a better understanding of childhood epilepsies worldwide. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target.
儿童癫痫是由异质性基础疾病引起的，其中约 40%的癫痫起源可归因于遗传因素。下一代测序（NGS）的应用彻底改变了分子诊断，使我们能够识别儿童癫痫的致病基因和变异。本研究的目的是应用 NGS 识别患有儿童癫痫的患者中的变异，扩大变异谱并发现潜在的治疗靶点。
在我们的研究中，通过结合临床外显子组和全外显子组测序，对 55 名病因不明的癫痫儿童进行分析。使用各种针对致病性和结构预测的计算算法来对新变异进行特征描述。
在 28 名患者中确定了癫痫的分子遗传学病因，总体诊断成功率为 50.9%。我们在 22 个与癫痫相关的不同基因中发现了变异，这些变异与描述的表型密切相关。在 5 名无亲缘关系的患者中发现了 SCN1A 基因变异，而在 ALDH7A1 和 KCNQ2 基因中发现了两次变异。在其他 19 个基因中，仅在单个患者中发现了变异。其中包括 ASH1L、CSNK2B、RHOBTB2 和 SLC13A5 等基因，这些基因最近才与癫痫相关。近一半（46.4%）诊断患者携带新变异。有趣的是，我们在 ALDH7A1、KCNQ2、PNPO、SCN1A 和 SCN2A 基因中发现了变异，这些变异导致我们研究中的 11 名儿童接受了基因导向的治疗决策，其中包括 4 名均携带新型 SCN1A 遗传变异的儿童。
所描述的新型变异将有助于更好地了解欧洲遗传图谱，而对基因型-表型相关性的深入了解将有助于更好地了解全球范围内的儿童癫痫。鉴于基于分子的方法的扩展，每个新发现的遗传变异都可能成为潜在的治疗靶点。
