The relationship between MT-ND3 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 6, 2023. MT-ND3 is located at m.10059-10404 of the mitochondrial DNA (mtDNA) genome and encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND3. Defects of this protein lead to complex I deficiency.
MT-ND3 was first reported in relation to primary mitochondrial disease in 2001 (PMID: 11456298). While various names have been given to the constellation of features seen in those with MT-ND3-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-ND3 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-ND3 was previously curated by this panel for its association with Leigh syndrome spectrum (LSS) on March 24, 2021 (SOP v8), with a final classification of definitive. This current curation for the association with primary mitochondrial disease includes cases with LSS.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes five variants (m.10134C>A, m.10158T>C, m.10191T>C, m.10197G>A, m.10254G>A) in 18 probands from 11 publications (PMIDs: 1928099, 14705112, 14764913, 17152068, 20202874, 25118196, 25384404, 11456298, 19458970, 30199507, 29237403). All curated variants were missense and three were recurrent (m.10158T>C, m.10191T>C, m.10197G>A). Affected individuals present with a broad phenotypic spectrum of clinical features including LSS; Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); lactic acidosis, epilepsia partialis continua (EPC), epileptic encephalopathy, dystonia, and optic atrophy. The age of onset is also highly variable, ranging from infantile to adult. Metabolic labs revealed elevated lactate in blood and cerebrospinal fluid (CSF). Muscle biopsy showed and complex I deficiency.
Heteroplasmy levels in affected individuals ranged from 76% - homoplasmic in muscle, 10% - homoplasmic in blood, as well as at >98% in various other tissues (fibroblasts, liver).
Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction and functional alteration in patient fibroblast cells (PMIDs: 27509854, 14705112).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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