MT-ND6

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: G2P

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-ND6* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 3, 2023. *MT-ND6* is located at m.14149-m.14673 of the mitochondrial DNA (mtDNA) genome and encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND6. Defects of this protein lead to complex I deficiency. *MT-ND6* was first reported in relation to primary mitochondrial disease in 1992 (PMID: 1634041). While various names have been given to the constellation of features seen in those with *MT-ND6*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-ND6* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT-ND6* 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 included six variants (m.14439G>A, m.14459G>A, m.14484T>C, m.14487T>C, m.14495A>G, m.14600G>A) in 21 probands from 16 publications (PMIDs: 15576045, 20019223, 21196529, 10894222, 14684687, 17535832, 19103152, 21749722, 23813926, 25356405, 14595656, 19062322, 11133798, 30741831, 21364701, 2018041). All curated variants were missense, and m.14484T>C and m.14487T>C are recurrent variants. Cybrid studies further supported the pathogenicity of several variants (PMIDs: 17535832, 25356405, 14595656). 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), and LSS phenotypes, as well as migraines, tremor, multiple sclerosis, and cardiac involvement. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsies revealed isolated complex I deficiency, and complex I and III deficiencies; and complex I deficiency was also seen in fibroblasts and liver. Metabolic screening labs showed elevated lactate and pyruvate in cerebrospinal fluid (CSF) and blood. Heteroplasmy levels in affected individuals ranged from 50% to >95% in skeletal muscle; 25% to >95% in blood, 76% to >95% in fibroblasts, and 65% to >95% in liver; and ranged in healthy family members from undetectable to 92% in blood, undetectable to 95% in urine, 14% to 95% in hair follicles, 16% to 68% in buccal, and was undetectable in muscle in healthy family members. Loss of function is implicated as the mechanism of disease. This gene-disease association is further supported by a known biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in patient derived cybrid cell lines (PMIDs: 27509854, 8622678), and a mouse model that recapitulates aspects of the primary mitochondrial disease phenotype (PMIDs: 23129651, 33536343). 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).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: Orphanet

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:0009723

Submitter: ClinGen

The relationship between *MT-ND6* and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 17, 2021. The *MT-ND6* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND6. Defects of this protein lead to complex I deficiency. The *MT-ND6* gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 2000 (PMID: 10894222). Evidence supporting the gene-disease relationship between *MT-ND6* and Leigh syndrome spectrum includes case-level data and experimental data. This curation included 4 variants in 17 cases (1 with m.14439G>A, 4 with m.14459G>A, 11 with m.14487T>C, and 1 with m.14600G>A) from 12 publications (PMIDs: 15576045, 20019223, 10894222, 14684687, 21196529, 17535832, 19103152, 21749722, 23813926, 25356405, 14595656, 19062322). 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 17). 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, functional alteration in non-patient cells, and animal models (PMIDs: 27509854, 8622678, 23129651, 33536343). 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).