Primary Mitochondrial Disease Expert Curation Panel

项目总结。原发性线粒体疾病是一种高度表型和遗传的疾病

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.