MT-ND4

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between *MT-ND4* and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 17, 2021. The *MT-ND4* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND4. Defects of this protein lead to complex I deficiency. The *MT-ND4* gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 2003 (PMID: 16120329). Evidence supporting the gene-disease relationship between *MT-ND4* and Leigh syndrome spectrum includes case-level data and experimental data. This curation included 2 variants in 6 cases (5 with m.11777C>A and 1 with m.11240C>T) from 5 publications (PMIDs: 16120329, 15576045, 20502985, 27761019, 32445240). Of note, while Gene Curation SOP Version 8 maxes case level missense variant total score at 7, the Mitochondrial Disease Gene Curation Expert Panel agreed the maximum score would be 12 given that the majority of pathogenic mitochondrial DNA variants are missense variants (the total score for genetic level evidence in this curation was 9). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. 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 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 17, 2021 (SOP Version 8).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0016814

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0020478

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010789

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: G2P