ClinGen Expert Curation Panel for the Epilepsies

ClinGen 癫痫专家组

• 批准号: 10459401
• 负责人: Ingo Helbig
• 金额: $ 37.63万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459401
• 关键词: Address; Affect; Antisense Oligonucleotides; Clinical; Communities; Complement; Decision Making; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Epilepsy; Etiology; Evaluation; Frequencies; Funding; Gene Combinations; Genes; Genetic; Genetic Predisposition to Disease; Glutamate Receptor; Goals; Grant; Guidelines; Human; Individual; Investigation; Laboratories; Medical Genetics; Modification; Molecular; Neurologic; Pathogenicity; Pharmaceutical Preparations; Pharmacology; Phenotype; Physicians; Potassium Channel; Procedures; Recommendation; Recurrence; Reporting; Research; Resistance; Resources; Role; SLC2A1 gene; Seizures; Site; Testing; Therapeutic; Variant; Work; actionable mutation; base; clinical decision-making; clinically actionable; clinically relevant; cohort; comorbidity; diagnostic panel; early onset; epileptic encephalopathies; gene therapy; genetic counselor; genetic panel test; genetic testing; genetic variant; novel; novel therapeutics; scale up; sustainability framework; variant of unknown significance

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.

项目总结/摘要 在过去的十年中，已经确定了100多种癫痫的遗传病因， 将以前知之甚少的疾病转化为不同的遗传病因， 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用于治疗 决定和开发新的疗法。这在发育和癫痫患者中尤其如此。 脑病，这是严重的，治疗抵抗性，早发性癫痫，经常与 伴有其他神经和非神经共病。癫痫患者的基因检测 在过去的几年里，有超过25，000人接受了诊断基因组测试。一 全面了解一个给定的基因-以及该基因的特定变体-是否实际上是 致病因素至关重要，但这方面的信息往往得不到。使用ClinGen框架，我们 我建议对与癫痫相关的基因进行系统的治疗，这些基因经常被 在临床实验室进行测试。对于一个基因子集，我们还将仔细评估特定的变异， 确定临床相关性。我们将聘请医生，分子遗传学家和遗传咨询师， 癫痫遗传学的专业知识，制定适当的指导方针，并将其系统地应用于基因， 变异策展工作。在我们对癫痫基因治疗的初步研究中，我们确定了10个基因， 通常包括在临床基因面板上，缺乏作为疾病基因的作用的证据，包括基因 例如已经广泛研究EFHC 1或SCN 9A。同样，在另一项研究中，我们发现， 大量的相关基因没有在诊断环境中进行常规测试。情况更 在评估变异时被放大，其中大多数从未被专家小组策划过。鉴于 癫痫基因中的致病变体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，并评估癫痫中基因-疾病关系的有效性， 策划这些基因的变异谱。