MT-ND2

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-ND2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 18, 2023. The *MT-ND2* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND2. Defects of this protein lead to complex I deficiency. *MT-ND2* was first reported in relation to maternally-inherited primary mitochondrial disease in 2001 (PMID: 11479733) in a family with Leber Hereditary Optic Neuropathy (LHON), however current population data suggests the variant reported in this case (m.4640C>A) is benign, so this case was excluded from this gene curation. Other associated features have been reported over time. While various names have been given to the constellation of features seen in those with *MT-ND2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-ND2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT-ND2* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on April 14, 2021 (SOP v8), with a final classification of limited. 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 included three unique variants (m.4681T>C, p.L71P; m.4810G>A, p.W114*; m.5132_5133del, fs) in three probands across three publications (PMIDs: 16738010, 15781840, 12192017). Single fiber testing and cybrid studies further supported the pathogenicity of several of these variants (PMIDs: 15781840, 16996290). Age of onset in affected individuals ranged from 9 months old to childhood. Clinical features in affected individuals included Leigh syndrome spectrum, myopathy, ophthalmoplegia, and ptosis. Muscle biopsies revealed ragged red fibers and complex I deficiency. Metabolic screening labs showed elevated lactate and creatine kinase (CK). Heteroplasmy levels were >95% in blood, fibroblasts, and muscle in the individual with Leigh syndrome spectrum. However in the other two individuals with predominantly myopathic features, the variant was present at >94% in muscle and undetectable in other tissues tested. The mechanism of disease appears to be loss of function. This gene-disease association is further supported by a known biochemical function shared with other genes associated with primary mitochondrial disease and a drosophila model (PMIDs: 33340416, 25085991). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 18, 2023 (SOP Version 9). This gene-disease relationship was reevaluated on July 14, 2025 by this Expert Panel. As a result of this reevaluation, the classification did not change.

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0016814

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between *MT-ND2* and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 14, 2021. The *MT-ND2* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND2. Defects of this protein lead to complex I deficiency. The* MT-ND2* gene was first reported in relation to maternally inherited Leigh syndrome spectrum (LSS) in 2007 (PMID: 16996290). The variant was first reported in the literature to be related to LSS in 2006 (PMID: 16738010), however insufficient detail was provided in the manuscript for this expert panel to confirm the diagnosis of LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one variant in one case (m.4681T>C) from one publication (PMID: 16996290). 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 biochemical function, functional alterations in patient cells, and animal models (PMIDs: 27977873, 16996290, 25085991). In summary, there is limited evidence to support this gene-disease relationship. Although the total score (6.5, rounds up to 7) falls in the moderate range, only one case with Leigh syndrome spectrum has been reported, therefore this gene-disease association can only reach a limited classification at this time. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel April 14, 2021 (SOP Version 8).