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Primary Mitochondrial Disease Expert Curation Panel

原发性线粒体疾病专家小组

基本信息

批准号：
10696934
负责人：
MARNI J FALK
金额：
$ 38.56万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/10696934
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 Consensus Counseling Data Set Databases Diet Disease Energy Metabolism Enrollment Fatigue 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 Qualifying Recurrence Reporting Research Personnel Resources Review Literature Specific qualifier value Standardization Stroke Structure Symptoms System Variant Work bioinformatics tool causal variant clinically actionable cofactor data resource disabling symptom disorder subtype exercise intolerance experience falls gene therapy genetic disorder diagnosis hearing impairment improved informatics tool medical complication mortality programs screening web portal

项目摘要

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.

项目摘要。原发性线粒体疾病是一种高度表型和遗传的疾病一组异质的进行性多系统疾病，影响 4,300 名儿童和成人中的 1 名，原因是细胞能量代谢受损。 PMD 患者平均会经历 16 种致残症状，其中许多是属于 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，可导致退化和/或代谢性中风、视力丧失和增加死亡。 PMD 是由数百个基因中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。 PMD 的准确基因诊断对于利用增强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），共同因素、改良饮食以及细胞或基因疗法。基因诊断对于改善病情也至关重要复发咨询和预防、医疗并发症筛查以及 FDA 临床试验纳入。然而，建立明确的 PMD 遗传病因仍然具有挑战性。自 2012 年以来，该项目由多个 PI 主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。自从 2017年，Multi-PI还获得了ClinGen线粒体疾病专家组的批准 NICHD 赞助的 U24 计划吸引了 30 多名国际线粒体疾病专家：a) 治疗 Leigh 综合征谱 (LSS) 疾病的基因疾病关联，b) 建立变体治疗可操作的核基因指南，以及 c) 解决管理 mtDNA 变体的独特挑战致病性，包括为 mtDNA 变异规范制定共识指南修订版。 2020年，我们出版了一本书“线粒体疾病基因纲要”，提供了易于获取的参考资料帮助临床医生和研究人员从基于基因的角度理解 256 个基因截至 2019 年 2 月，ClinVar 中发现了与 PMD 相关的变异。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表型扩展到策划工作，以满足更广泛的社区对基因疾病协会专家小组策划的需求和 mtDNA 变异对所有 PMD 的两个具体目标的致病性。在目标 1 中，我们建议完成基因- 疾病协会专家小组整理了 256 个具有与 PMD 相关的 ClinVar 变异的基因。在目标 2 中，我们建议对具有报告致病性的变异进行 mtDNA 变异疾病专家小组的管理， ClinVar 中针对 PMD 的不确定或相互矛盾的断言，并与 ClinGen 领导层密切合作以优化 ClinGen 基础设施和信息学接口，支持使用 ClinGen 批准的 mtDNA 变异管理 mtDNA 变异管理规范。这项工作将提供一套明确的、专家策划的 PMD 基因，并在 ClinGen 框架内创建持久的 mtDNA 基因组变异专家管理流程。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.

DOI：
10.1002/humu.24107
发表时间：
2020-12
期刊：
Human mutation
影响因子：
3.9
作者：
McCormick EM;Lott MT;Dulik MC;Shen L;Attimonelli M;Vitale O;Karaa A;Bai R;Pineda-Alvarez DE;Singh LN;Stanley CM;Wong S;Bhardwaj A;Merkurjev D;Mao R;Sondheimer N;Zhang S;Procaccio V;Wallace DC;Gai X;Falk MJ
通讯作者：
Falk MJ

Community Consensus Guidelines to Support FAIR Data Standards in Clinical Research Studies in Primary Mitochondrial Disease.