ClinGen Expert Curation Panel for the Epilepsies

项目摘要/摘要 在过去的十年里，在癫痫中已经确定了100多种遗传原因，使一组人 以前知之甚少的疾病转化为不同的遗传病因，可识别高达30%-40% 受影响的个人。关于遗传病因学的信息正在并将越来越多地被用于治疗 决定和开发新的治疗方法。在发育期和癫痫患者中尤其如此。 脑病，这是一种严重的、耐药的、经常与之相关的早发性癫痫 有额外的神经性和非神经性共病。对癫痫患者进行基因测试 在过去的几年里，有25,000人接受了诊断基因小组测试。一个 对给定基因--以及该基因中的特定变异--是否真的有全面的理解 致病因素很重要，但这方面的信息往往无法获得。使用Clingen框架，我们 建议对已报告的与癫痫相关的和经常发生的基因进行系统的筛选 在临床实验室进行检测。对于基因的一个子集，我们还将仔细评估特定的变异以 确定临床相关性。我们将聘请内科医生、分子遗传学家和遗传顾问 癫痫遗传学方面的专业知识，以制定适当的指南，并系统地将其应用于基因和 不同的策展工作。在我们关于癫痫基因管理的初步工作中，我们确定了10个基因，它们是 通常包括在缺乏疾病基因作用证据的临床基因小组中，包括基因 如EFHC1或SCN9A已进行了广泛研究。同样，在另一项研究中，我们发现一种 在诊断环境中，大量的相关基因没有进行常规检测。情况平分秋色 在评估变种时被放大，其中大多数从未由专家小组进行管理。考虑到 癫痫基因的致病变异越来越多地用于临床和治疗决策， 我们的目标是解决这一关键差距，并评估癫痫患者基因-疾病关系的有效性。 整理这些基因的变异谱。

PROJECT SUMMARY/ABSTRACT Over the past decade, more than 100 genetic etiologies have been identified in the epilepsies, turning a group of previously poorly understood conditions into distinct genetic etiologies that can be identified in up to 30-40% of affected individuals. Information about genetic etiology is and will be increasingly used to make treatment decisions and to develop novel therapies. This is especially true in the developmental and epileptic encephalopathies, which are severe, treatment resistant, early-onset epilepsies that are frequently associated with additional neurological and non-neurological co-morbidities. Genetic testing in the epilepsies is performed at scale with > 25,000 individuals having undergone diagnostic gene-panel testing in the last few years. A comprehensive understanding of whether a given gene – as well as specific variants in that gene – is in fact disease-causing is critical, but this information is frequently not available. Using the ClinGen framework, we propose to perform systematic curation of genes that are reported associated with epilepsy and are frequently testing in clinical laboratories. For a subset of genes, we will also carefully evaluate specific variants to determine clinical relevance. We will engage physicians, molecular geneticists and genetic counselors with expertise in epilepsy genetics to develop appropriate guidelines and apply them systematically to the gene and variant curation effort. In our preliminary work on epilepsy gene curation, we identified 10 genes that are commonly included on clinical gene panels that lack evidence for a role as a disease gene, including genes such as EFHC1 or SCN9A that have extensively researched. Likewise, in a separate study, we found that a substantial number of relevant genes are not tested for routinely in a diagnostic setting. The situation is even magnified when assessing variants, most of which have never been curated by expert panels. Given that disease-causing variants in epilepsy genes are increasingly used for clinical and therapeutic decision-making, we aim to address this critical gap and assess the validity of gene-disease relationships in the epilepsies and curate the spectrum of variants in these genes.