MT-ND5

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010790

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010789

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: G2P

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0016814

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MT-ND5 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 24, 2021. The MT-ND5 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND5. Defects of this protein lead to complex I deficiency. The MT-ND5 gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 2002 (PMID: 11938446). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 6 variants in 21 cases (1 with m.12706T>C, 1 with m.13042G>A, 1 with m.13063G>A, 9 with m.13094T>C, 1 with m.13511A>T, and 8 with m.13513G>A) from 8 publications (PMIDs: 17400793, 11938446, 12624137, 18495510, 23918514, 17535832, 29506874, 23034978). 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. 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 alterations in patient cells, and functional alteration in non-patient cells (PMIDs: 27509854, 32366037, 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 24, 2021 (SOP Version 8).