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一般性的由于影响4,300名儿童和成人中有1个的进步，多系统疾病的异质群细胞能量代谢受损。 PMD患者平均会经历16种禁用症状，许多症状属于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敏感性，精确的回归和/或代谢中风，视力丧失和增加死亡。 PMD是由致病性变异引起的遗传性疾病核和线粒体DNA（mtDNA）基因组。 PMD的准确遗传诊断对于利用提高起启动或避免特定药物（例如抗癫痫和麻醉剂）的起作用性，共同因素，改良饮食以及细胞或基因疗法。遗传诊断也必须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，确定确定的PMD遗传病因仍然受到挑战。自2012年以来，该项目多PI领导国际线粒体疾病序列数据资源（MSEQDR）联盟组织和组织策展PMD基因组知识，信息工具和标准化本体学定义的表型。自从 2017年，多PIS也获得了通过固执的线粒体疾病专家小组的认可 NICHD赞助的U24计划与30多个国际线粒体疾病专家参与：a）基因 - 疾病协会的策展Leigh综合征谱（LSS）疾病，b）建立变体策划可操作的核基因指南，c）解决策划mtDNA变体的独特挑战致病性，包括创建MTDNA变体规范的共识指南修订。在2020年，我们出版了一本书《线粒体疾病基因纲要》，该书提供了容易获得的参考从基于基因的256个基因的基于基因的角度来理解临床医生和研究人员的助手PMD 截至2019年2月，与Clinvar的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旨在从综合征和有组织的表型中扩展策划努力承担更广泛的社区需求，以实现基因疾病协会的专家小组策划在两个特定目标中，所有PMD的mtDNA变异致病性。在AIM 1中，我们建议完成基因疾病协会的专家面板策划256个基因，具有与PMD相关的Clinvar变体。在AIM 2中，我们建议用报告的致病性，对于PMD的Clinvar中的不确定或相互矛盾的断言，并与Clingen领导力紧密合作以优化使用克林根批准 mtDNA变体策展规范。这项工作将提供一套确定的专家策划的PMD基因，并创建持久的过程，以用于在克林根框架内MTDNA基因组变体的专家策划。

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.