Expert curation of pediatric mitochondrial Leigh-like syndrome genes and variants

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PROJECT SUMMARY. Mitochondrial disease is a highly phenotypically and genetically heterogeneous group of progressive, multi-system disorders affecting 1 in 4,300 people due to impaired cellular energy metabolism. Many mitochondrial disorders fall within the NICHD high priority clinical domain, which involves a broad spectrum of neurodevelopmental disabilities including autism. The common pediatric mitochondrial disease presentations termed Leigh syndrome (LS) or Leigh-like syndrome (LLS), which can be caused by mutations in approximately 90 genes across both nuclear and mitochondrial genomes, are linked with intellectual and neurodevelopmental disabilities, infection susceptibility that often precipitates neurodevelopmental regression, metabolic strokes in basal ganglia and deep brain structures at any point in childhood including, in some cases, in the newborn period that is associated with primary lactic acidosis from birth and early demise, with an overall 35% mortality in childhood. Establishing an accurate genetic diagnosis of these diverse pediatric mitochondrial encephalopathy syndromes is critically important, as an increasing number have clinical actionability involving initiation or avoidance of specific medications, cofactors, or diets. Accurate diagnosis currently remains challenging, as there is no expertly-curated and comprehensive catalogue of pathogenic LS, LLS, and other gene mutations to guide diagnosis and clinical actionability. Since 2012, the project PIs have co-led the international Mitochondrial Disease Sequence Data Resource (MSeqDR) consortium to organize and curate mitochondrial disease genomic knowledge, analysis and sharing tools, and phenotypes. This organized MSeqDR community structure and committed international expertise is now poised to collaboratively curate genes and variants relevant to the most prevalent and treatable mitochondrial LS and LLS pediatric encephalopathy syndromes using ClinGen resources and curation tools. Aim 1. To complete gene-disease association expert curation for all pediatric mitochondrial encephalopathy syndromes with neurodevelopmental disability in the Leigh and Leigh-like spectrum. We will utilize the ClinGen gene curation tools and frameworks to review the gene-disease relationship for approximately 90 genes that cause LS, LLS, and other pediatric mitochondrial encephalopathy syndromes. We have brought together 32 leading international experts from 11 countries to collaboratively analyze all relevant data and achieve consensus in this important gene-disease curation effort. Aim 2. To expertly curate variants in the most prevalent and treatable pediatric-onset mitochondrial encephalopathy nuclear and mtDNA genes. Nuclear genes causing the most prevalent (SURF1, POLG, FBXL4) and treatable (SLC19A3, BTD, PDSS2, PDHA1, TPK1, ACAD9, ETHE1, HIBCH) pediatric-onset LS and LLS will be prioritized. In addition, our global network of leading mtDNA disease experts will evaluate the mtDNA variant pathogenicity assertions for mtDNA- associated pediatric LS and LLS genes, starting with the 3 most common causes (ATP6, ND5, MT-TL).