Human Genetics ( IF 5.3 ) Pub Date : 2021-09-21 , DOI: 10.1007/s00439-021-02370-4 Georgia Sarquella-Brugada 1, 2 , Anna Fernandez-Falgueras 3, 4, 5 , Sergi Cesar 2 , Elena Arbelo 4, 6 , Mónica Coll 3, 4 , Alexandra Perez-Serra 3, 4 , Marta Puigmulé 3, 4 , Anna Iglesias 3, 4 , Mireia Alcalde 3, 4 , Marta Vallverdú-Prats 3 , Victoria Fiol 2 , Carles Ferrer-Costa 3 , Bernat Del Olmo 3, 4 , Ferran Picó 3, 4 , Laura Lopez 3, 4 , Ana García-Alvarez 4, 6 , Paloma Jordà 4, 6 , Coloma Tiron de Llano 5 , Rocío Toro 7 , Simone Grassi 8 , Antonio Oliva 8 , Josep Brugada 2, 4, 6 , Ramon Brugada 1, 3, 4, 5 , Oscar Campuzano 1, 3, 4
A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.
中文翻译:
与遗传性离子通道病相关的罕见变异的临床影响:5 年更新
在临床翻译之前,正确解释罕见变异的致病性至关重要。新数据的持续添加可能会修改以前的变体分类;但是,需要重新分析的频率仍未确定。我们旨在广泛重新分析与 5 年前最初分类的遗传性离子通道病相关的罕见变异及其临床影响。2016 年,根据美国医学遗传学和基因组学学院的建议,通过基因分析鉴定出的罕见变异被分类。五年后,我们按照相同的建议重新分类了相同的变体,但包括新的可用数据。讨论了潜在的临床意义。我们的队列包括 2016 年诊断的 49 例遗传性离子通道病。更新显示有 18 例。36% 的变体改变分类主要是由于改进的全局频率数据。重新分类主要发生在与通道病相关的少数基因中。如今,相似百分比的变异仍然是有害的,位于主要的已知基因中(SCN5A、KCNH2和KCNQ1 )。2016 年,69.38% 的变异被归类为未知意义,但现在,53.06% 的变异被归类为此类,仍然是最常见的组。在将遗传数据转化为临床后,没有对管理进行修改。5 年后,近 20% 的与遗传性离子通道病相关的罕见变异被重新分类。这支持执行自上次分类以来不超过 5 年的定期重新分析。有必要使用新的可用数据,特别是在全球频率和家庭隔离方面。如果发现分类发生重大变化,罕见变异的个性化临床翻译对管理至关重要。