Submission Details

The relationship between MT-ND4 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 6, 2023. MT-ND4 is located at m.10760-12137 of the mitochondrial DNA (mtDNA) genome and encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND4. Defects of this protein lead to complex I deficiency.

MT-ND4 was first reported in relation to primary mitochondrial disease in 1988 (PMID: 3201231). While various names have been given to the constellation of features seen in those with MT-ND4-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-ND4 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-ND4 was previously curated by this panel for its association with Leigh syndrome spectrum (LSS) on May 17, 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 four variants (m.11240C>T, m.11406T>A, m.11777C>A, m.11778G>A) in nine probands in eight publications (PMIDs: 12707444, 16120329, 15576045, 20502985, 27761019, 32445240, 32659360, 3201231). Cybrid studies further supported the pathogenicity of several variants (PMIDs: 16120329, 27761019).

Affected individuals present with a broad phenotypic spectrum of clinical features including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; cerebellar ataxia, migraines, regression, developmental delay, leukoencephalopathy, myoclonus, seizures, stroke-like episodes, cognitive decline, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, ophthalmoplegia, short stature, and hypertrophic cardiomyopathy. Age of onset varied from infancy to adulthood. Metabolic labs revealed elevated lactate in blood and cerebrospinal fluid (CSF). Muscle biopsy showed COX-negative fibers and complex I deficiency. Heteroplasmy levels in affected individuals ranged from 60% - 83% in muscle, 40% - 80% in blood, and 76% - 78% in myoblasts, as well as from 57% - 73% in various other tissues (fibroblasts, liver, urine, buccal). Of note, the m.11778G>A common LHON variant was reported in affected individuals in the homoplasmic and heteroplasmic states.

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 cells (PMIDs: 27509854, 16120329).

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).