Submission Details

The relationship between MT-ND5 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 3, 2023. MT-ND5 is located at m.12337-m.14148 of the mitochondrial DNA (mtDNA) genome and encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND5. Defects of this protein lead to complex I deficiency.

MT-ND5 was first reported in relation to primary mitochondrial disease in 1993 (PMID: 8213825). While various names have been given to the constellation of features seen in those with MT-ND5-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-ND5 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-ND5 was previously curated by this panel for its association with Leigh syndrome spectrum (LSS) on May 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 six variants (m.12706T>C, m.13042G>A, m.13063G>A, m.13094T>C, m.13511A>T, m.13513G>A) in 24 probands from 11 publications (PMIDs: 17400793, 11938446, 12624137, 18495510, 23918514, 17535832, 29506874, 23034978, 16816025, 9299505, 18977334). All curated variants were missense, including two recurrent variants (m.13513G>A and m.13094T>C). Cybrid studies further supported the pathogenicity of several variants (PMIDs: 17535832, 18977334). Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; myoclonus epilepsy, ragged red fibers (MERRF); and cardiomyopathy. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsies variably revealed ragged red fibers, isolated complex I deficiency, and variable combined deficiencies of complexes I, III, and/or IV. Metabolic screening labs showed elevated lactate in cerebrospinal fluid (CSF) and blood and urinary excretion of Krebs cycle intermediates. Heteroplasmy levels in affected individuals ranged from 28% - 90% in skeletal muscle, 23% to 77% in blood, undetectable to 90% in fibroblasts, 51% - 81% in urine; and ranged in healthy family members from undetectable to 20% in blood, undetectable to 25% to 95% in hair follicles, undetectable to 4-6% muscle, and ranged from 27%-45% in other tissues such as urine and buccal samples in healthy family members.

Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by a known biochemical function shared with other genes associated with primary mitochondrial disease and functional alteration in patient iPSC derived neurons and cybrid cell lines (PMIDs: 27509854, 26159306).

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 May 3, 2023 (SOP Version 9).