Primary Mitochondrial Disease Expert Curation Panel

原发性线粒体疾病专家小组

• 批准号: 10173437
• 负责人: MARNI J FALK
• 金额: $ 40.46万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173437
• 关键词: Address; Adult; Affect; Anesthetics; Antiepileptic Agents; Benign; Biochemical; Biochemical Pathway; Blindness; Books; Categories; Cell Therapy; Child; Childhood; ClinVar; Clinical; Clinical Trials; Communities; Conflict (Psychology); Consensus; Counseling; Data Set; Databases; Diet; Diet therapy; Disease; Energy Metabolism; Enrollment; Fatigue; Gap Junctions; Genes; Genetic Predisposition to Disease; Genome; Genomics; Goals; Grant; Guidelines; Heart Diseases; Hematology; Hereditary Disease; Immune System Diseases; Impairment; Individual; Infection; Informatics; Infrastructure; Inherited; Intellectual functioning disability; International; Knowledge; Leadership; Leigh Disease; Link; Manuals; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Muscle Weakness; National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disability; Neurologic; Nuclear; Ontology; Organ; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Prevention; Procedures; Process; Proteome; Publishing; Recurrence; Reporting; Research Personnel; Resources; Review Literature; Specific qualifier value; Standardization; Stroke; Structure; Symptoms; Syndrome; Variant; Work; base; bioinformatics tool; causal variant; clinically actionable; data resource; disabling symptom; disorder subtype; exercise intolerance; experience; falls; gene therapy; genetic disorder diagnosis; genetic variant; hearing impairment; improved; informatics tool; medical complication; mortality; programs; screening; web portal

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.

项目总结。原发性线粒体疾病是一种高度表型和遗传学的疾病。 由于以下原因，每4,300名儿童和成人中就有1名患有进行性多系统疾病的异质性群体 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的高度优先事项，包括智力或神经发育障碍 具有感染易感性，可加速退行性和/或代谢性中风、视力丧失和增加 死亡率。PMD是由两者数百个基因中的任何一个的致病变异引起的遗传性疾病 核和线粒体DNA(MtDNA)基因组。准确的PMD基因诊断对于 利用更高的可操作性来启动或避免特定药物(如抗癫痫药物和麻醉药)，共同 因子、改良饮食和细胞或基因疗法。基因诊断也是改进的当务之急 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的确切遗传病因仍然具有挑战性。自2012年以来，多PI项目一直在领导 国际线粒体疾病序列数据资源(MSeqDR)联盟将组织和 整理PMD基因组知识、信息学工具和标准化的本体定义的表型。自.以来 2017年，多PI还通过 NICHD赞助的U24项目，聘请了30多名国际线粒体疾病专家：a) 对Leigh综合征谱(LSS)障碍进行基因-疾病关联的管理，b)建立不同的管理 可操作核基因指南，以及c)解决管理mtDNA变异的独特挑战 致病性，包括为mtDNA变体规范创建一致的指南修订版。2020年，我们 出版了一本名为《线粒体疾病基因概要》的书，为 帮助临床医生和研究人员从基于基因的角度对256个具有 截至2019年2月，ClinVar中与PMD相关的变体。利用这些重大进步，我们的克莱根 线粒体疾病专家小组现在的目标是从综合征和以器官为重点的表型扩大 承担更广泛社区的监管工作需要专家小组对基因-疾病关联进行监管 MtDNA变异对所有PMD的致病力有两个特定目的。在目标1中，我们建议完成基因- 疾病协会专家小组对256个带有与PMD相关的ClinVar变体的基因进行了管理。在目标2中， 我们建议对报告的致病基因变异进行线粒体DNA变异疾病专家小组的筛选， 针对PMD的ClinVar中不确定或相互冲突的断言，并与Clingen领导层密切合作，以优化 Clingen基础设施和信息接口，支持使用Clingen批准的mtDNA变体管理 线粒体DNA不同的管理规范。这一努力将提供一套明确的、由专家策划的PMD基因， 并为Clingen框架内线粒体DNA基因组变异的专家管理创造持久的过程。