Exploring the Genetic Etiology of Pediatric Epilepsy: Insights from Targeted Next-Generation Sequence Analysis.

IF 0.9 4区医学 Q4 GENETICS & HEREDITY

Molecular Syndromology Pub Date : 2025-04-01 Epub Date: 2024-08-29 DOI:10.1159/000540762

Ozden Ozturk, Murat Ozturk, Kubra Ates, Zeynep Esener, Naile Nisa Erguven, Bilge Ozgor, Serdal Gungor, Ahmet Sigirci, Ibrahim Tekedereli

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引用次数: 0

Abstract

Introduction: Epilepsy is a group of neurologic disorders with clinical and genetic heterogeneity. Epilepsy often affects children; thus, early diagnosis and precise treatment are vital to protecting the standard of life of a child. Progress in epilepsy-related gene discovery has caused enormous novelty in specific epilepsy diagnoses. Genetic testing using next-generation sequencing is now reachable, leading to higher diagnosis ratios and understanding of the disease's underlying mechanisms. The study's primary aim was to identify the genetic etiology based on targeted next-generation sequence analysis data and to calculate the diagnostic value of the epilepsy gene panel in the 0-17 age-group diagnosed with epilepsy. The secondary aim was to demonstrate the significance of periodic reinterpretation of variant of uncertain significance (VUS) variants and genotype-phenotype correlation.

Methods: This retrospective study comprised 107 patients with epilepsy aged 8 months to 17 years, for whom a targeted gene panel covered 110 genes. VUS variants were reanalyzed, and genotype-phenotype correlation was performed.

Results: In the initial evaluation, causal variants were described in 23 patients (21.5%). After reinterpretation of VUS, we detected causal variants in 30 out of 107 patients (28%). By reinterpreting the VUS and evaluating genotype-phenotype correlations, we enhanced our diagnostic value by 30.32%. After reinterpretation of VUS variants, the ACMG classification of 36 variants, including 15 benign (31%), 15 likely benign (31%), 5 likely pathogenic (10%), and 1 pathogenic (2%), were redefined. We most frequently detected causal variants in TSC2 (n = 5), GRIN2A (n = 4), and ALDH7A1 (n = 4) genes.

Conclusion: The predictive value for epilepsy panel testing was 28% in the cohort. Our study revealed the importance of reanalysis of VUS variants and contributed to enriching the mutation spectrum in epilepsy.

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探索小儿癫痫的遗传病因：来自下一代靶向序列分析的见解。

简介：癫痫是一组具有临床和遗传异质性的神经系统疾病。癫痫常影响儿童；因此，早期诊断和精确治疗对于保护儿童的生活水平至关重要。癫痫相关基因发现的进展为特定的癫痫诊断带来了巨大的新颖性。现在可以使用下一代测序技术进行基因检测，从而提高诊断率并了解疾病的潜在机制。该研究的主要目的是基于靶向下一代序列分析数据确定遗传病因，并计算癫痫基因面板在0-17岁被诊断为癫痫的年龄组中的诊断价值。第二个目的是证明周期性重新解释不确定显著性变异（VUS）变异和基因型-表型相关性的重要性。方法：本回顾性研究纳入107例8个月至17岁的癫痫患者，目标基因面板涵盖110个基因。重新分析VUS变异，并进行基因型-表型相关性分析。结果：在初步评估中，23例患者（21.5%）描述了因果变异。在重新解释VUS后，我们在107例患者中检测到30例（28%）的因果变异。通过重新解释VUS和评估基因型-表型相关性，我们的诊断价值提高了30.32%。重新解释VUS变异后，重新定义了36个变异的ACMG分类，包括15个良性（31%），15个可能良性（31%），5个可能致病性（10%）和1个致病性（2%）。我们最常检测到的因果变异是TSC2 （n = 5）、GRIN2A （n = 4）和ALDH7A1 （n = 4）基因。结论：癫痫面板检测在队列中的预测价值为28%。我们的研究揭示了重新分析VUS变异的重要性，并有助于丰富癫痫的突变谱。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Syndromology Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

1.70

自引率

9.10%

发文量

期刊介绍： ''Molecular Syndromology'' publishes high-quality research articles, short reports and reviews on common and rare genetic syndromes, aiming to increase clinical understanding through molecular insights. Topics of particular interest are the molecular basis of genetic syndromes, genotype-phenotype correlation, natural history, strategies in disease management and novel therapeutic approaches based on molecular findings. Research on model systems is also welcome, especially when it is obviously relevant to human genetics. With high-quality reviews on current topics the journal aims to facilitate translation of research findings to a clinical setting while also stimulating further research on clinically relevant questions. The journal targets not only medical geneticists and basic biomedical researchers, but also clinicians dealing with genetic syndromes. With four Associate Editors from three continents and a broad international Editorial Board the journal welcomes submissions covering the latest research from around the world.