Primary Mitochondrial Disease Expert Curation Panel

项目摘要。原发性线粒体疾病是一种高度表型和遗传性的 一组异质性进行性多系统疾病，影响1/4300的儿童和成人， 细胞能量代谢受损PMD患者平均经历16种致残症状，许多 属于NICHD、NINDS和NEI的高度优先级，包括智力或神经发育障碍 具有感染易感性，可加速退化和/或代谢性中风、视力丧失和增加 mortality. PMD是一种遗传性疾病，由两种疾病中数百个基因中的任何一个致病变异引起。 核和线粒体DNA（mtDNA）基因组。PMD的准确遗传诊断是必不可少的， 利用增加的可操作性来启动或避免特定药物（例如抗癫痫药和麻醉药）， 因子、改良饮食和细胞或基因疗法。基因诊断也是改善 复发咨询和预防、医疗并发症筛查和FDA临床试验纳入。然而， 确定PMD的遗传病因仍然具有挑战性。自2012年以来，Multi-PI项目一直在领导 国际线粒体疾病序列数据资源（MSeqDR）联盟组织和 管理PMD基因组知识、信息学工具和标准化本体定义的表型。以来 2017年，Multi-PI还获得了ClinGen线粒体疾病专家小组的批准， NICHD赞助的U24项目，吸引了30多名国际线粒体疾病专家参与：a） 筛选Leigh综合征谱系（LSS）疾病的基因-疾病关联，B）建立变异型筛选 可操作的核基因的指导方针，以及c）解决策划mtDNA变异的独特挑战 致病性，包括创建共识指南修订mtDNA变异规范。2020年我们 出版了一本书，“线粒体疾病基因纲要”，提供了一个容易获得的参考， 帮助临床医生和研究人员从基于基因的角度理解PMD， 截至2019年2月，ClinVar中与PMD相关的变体。利用这些重大进展，我们的ClinGen 线粒体疾病专家小组现在的目标是从综合征和器官集中的表型扩展 策展工作，以应对更广泛的社区对基因-疾病关联专家小组策展的需求 线粒体DNA变异体对两个特异性目的的PMD致病性的研究。在目标1中，我们建议完成基因- 疾病协会专家小组对256个具有与PMD相关的ClinVar变体的基因进行了管理。在目标2中， 我们建议进行mtDNA变异-疾病专家组对报告的致病性变异的治疗， 在ClinVar for PMD中的不确定或冲突断言，并与ClinGen领导层密切合作， ClinGen基础设施和信息学接口，支持使用ClinGen批准的 线粒体DNA变异体管理规范。这项工作将提供一个明确的，专家策划的PMD基因集， 并在ClinGen框架内为mtDNA基因组变异的专家策展创建持久的流程。

PROJECT SUMMARY. Primary mitochondrial disease is a highly phenotypically and genetically heterogeneous group of progressive, multi-system disorders affecting 1 in 4,300 children and adults due to impaired cellular energy metabolism. PMD patients on average experience 16 disabling symptoms, many falling within high priority to NICHD, NINDS, and NEI, including intellectual or neurodevelopmental disabilities with infection susceptibility that precipitates regression and/or metabolic strokes, vision loss, and increased mortality. PMD are inherited disorders caused by pathogenic variants in any of hundreds of genes across both nuclear and mitochondrial DNA (mtDNA) genomes. Accurate genetic diagnoses of PMD are essential to harness increased actionability to initiate or avoid specific medications (e.g. anti-epileptics & anesthetics), co- factors, modified diets, and cellular or gene therapies. Genetic diagnosis is also imperative for improved recurrence counseling and prevention, medical complication screening, and FDA clinical trial inclusion. Yet, establishing definitive PMD genetic etiologies remains challenging. Since 2012, the project Multi-PIs have led the international Mitochondrial Disease Sequence Data Resource (MSeqDR) consortium to organize and curate PMD genomic knowledge, informatics tools, and standardized ontology-defined phenotypes. Since 2017, the Multi-PIs have also gained approval as the ClinGen Mitochondrial Disease Expert Panel through the NICHD-sponsored U24 program that engaged more than 30 international mitochondrial disease experts to: a) curate Leigh syndrome spectrum (LSS) disorders for gene-disease association, b) establish variant curation guidelines for actionable nuclear genes, and c) address the unique challenges of curating mtDNA variant pathogenicity, including creation of consensus guideline revisions for mtDNA variant specification. In 2020, we published a book, “Mitochondrial Disease Genes Compendium” that provides a readily accessible reference to aide PMD understanding by clinicians and researchers from a gene-based perspective for 256 genes that had variants associated with PMD in ClinVar as of Feb 2019. Harnessing these major advances, our ClinGen Mitochondrial Disease Expert Panel now aims to expand from syndromic and organ-focused phenotype curation efforts to take on the broader community need for expert panel curation of Gene-Disease associations and mtDNA variant pathogenicity for all PMD in two Specific Aims. In Aim 1, we propose to complete Gene- Disease association expert panel curation of 256 genes with ClinVar variants associated with PMD. In Aim 2, we propose to perform mtDNA variant-disease expert panel curation of variants with reported pathogenic, uncertain, or conflicting assertions in ClinVar for PMD, and work closely with ClinGen leadership to optimize ClinGen infrastructure and informatics interfaces to support mtDNA variant curation using ClinGen-approved mtDNA variant curation specifications. This effort will provide a definitive, expert-curated set of PMD genes, and create lasting processes for expert curation of mtDNA genome variants within the ClinGen framework.