PDF(Pubmed)
Abstract：
BACKGROUND: Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders.
METHODS: Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts.
RESULTS: We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%.
CONCLUSIONS: The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.
METHODS: Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts.
RESULTS: We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%.
CONCLUSIONS: The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.
摘要：
背景：遗传诊断支持遗传性心律失常性疾病的诊断，但是不确定意义(VUS)的变体会使事情复杂化，强调需要定期重新评估。我们的研究旨在重新分析不同基因中的罕见变异，以减少VUS诊断，从而改善心律失常患者的风险分层和个性化治疗。
方法：使用Sanger测序和下一代测序（NGS）分析基因组DNA。使用各种数据库和计算机预测工具对数据进行评估，并由两名独立专家根据当前的ACMG标准进行分类。
结果：我们在30个基因中鉴定出53个VUS，其中17个变异体(32%)被重新分类。分别有13％被降级为可能的良性（LB）和良性（B），6％被升级为可能的致病性（LP）。重新分类主要发生在2017-2019年最初分类的变体中，比率从50％到60％不等。
结论：结果支持常规VUS重新分类很重要的假设，因为它为基因诊断提供了新的见解，使患者受益并指导治疗方法。
方法：使用Sanger测序和下一代测序（NGS）分析基因组DNA。使用各种数据库和计算机预测工具对数据进行评估，并由两名独立专家根据当前的ACMG标准进行分类。
结果：我们在30个基因中鉴定出53个VUS，其中17个变异体(32%)被重新分类。分别有13％被降级为可能的良性（LB）和良性（B），6％被升级为可能的致病性（LP）。重新分类主要发生在2017-2019年最初分类的变体中，比率从50％到60％不等。
结论：结果支持常规VUS重新分类很重要的假设，因为它为基因诊断提供了新的见解，使患者受益并指导治疗方法。
