# Primary Mitochondrial Disease Expert Curation Panel

> **NIH NIH U24** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $385,581

## Abstract

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...

## Key facts

- **NIH application ID:** 10480773
- **Project number:** 5U24HD093483-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** MARNI J FALK
- **Activity code:** U24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,581
- **Award type:** 5
- **Project period:** 2017-08-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480773

## Citation

> US National Institutes of Health, RePORTER application 10480773, Primary Mitochondrial Disease Expert Curation Panel (5U24HD093483-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10480773. Licensed CC0.

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