Submission Details

The relationship between MT-ND1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 3, 2023. MT-ND1 is located at m.3307-m.4262 of the mitochondrial DNA (mtDNA) genome and encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND1. Defects of this protein lead to complex I deficiency.

MT-ND1 was first reported in relation to primary mitochondrial disease in 1991 (PMID: 1928099). While various names have been given to the constellation of features seen in those with MT-ND1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-ND1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-ND1 was previously curated by this panel for its association with Leigh syndrome spectrum (LSS) on April 12, 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 eight variants (m.3460G>A, m.3481G>A, m.3688G>A, m.3697G>A, m.3890G>A, m.3902_3908delinsGCAAGGT, m.3928G>C, m.3946G>A) in 13 probands from 12 publications (PMIDs: 1928099, 15466014, 10775530, 16492986, 18504678, 18977334, 23246842, 24063851, 27017994, 24830958, 31996177, 17535832). With the exception of one small inversion (m.3902_3908delinsGCAAGGT) all variants were missense. There were four recurrent variants (m.3697G>A, m.3890G>A, m.3635G>A, m.3902_3908delinsGCAAGGT). Cybrid studies further supported the pathogenicity of several variants (PMIDs: 1928099, 15466014, 16492986, 18977334, 23246842). 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, and exercise intolerance phenotypes. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsies variably revealed focal subsarcolemmal accumulation of mitochondria, ragged red fibers, and isolated complex I deficiency. Metabolic screening labs showed elevated lactate and pyruvate in cerebrospinal fluid (CSF) and blood. Heteroplasmy levels in affected individuals ranged from 36% to homoplasmic in skeletal muscle, undetectable to homoplasmic in blood, 12% to homoplasmic in fibroblasts, 70% - 96% in urine, 87% - 95% in liver, and ranged from 85% - 93% in other tissues such as heart, hair follicles, and buccal sample; and ranged in healthy family members from undetectable to 3% in blood, undetectable to 3% in urine, 14% to 95% in hair follicles, 16% to 68% in buccal, and was undetectable in fibroblasts and muscle 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 cybrid cell lines and in an Escherichia coli model system (PMIDs: 27509854, 22079202, 17535832).

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 April 3, 2023 (SOP Version 9).