Submission Details

The relationship between MT-ND4L and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 20, 2022. The MT-ND4L gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND4L. Defects of this protein lead to complex I deficiency. This gene is located at position m.10470-10766 of the mitochondrial DNA (mtDNA) heavy strand. Of note, seven nucleotides overlap the last three codons of MT-ND4L and the first three codons of MT-ND4. No pathogenic variants have been reported in this overlap region.

MT-ND4L was first reported in relation to maternally inherited primary mitochondrial disease in two families with Leber Hereditary Optic Neuropathy (LHON) in 1995 (PMID: 8680405). These families were first reported in 1994 (PMID: 7977345), but the genetic etiology was not identified until 1995. In subsequent work, cybrid analyses were performed for m.10663T>C which showed a mild impact on complex I function similar to the order of magnitude seen with m.14484T>C, one of the three most common LHON-associated variants (PMID: 11935318). While various names have been given to the constellation of features seen in those with MT-ND4L-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-ND4L phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven probands with m.10063T>C across five publications, all of whom had LHON (PMIDs: 8680405, 11935318, 17003408, 22879922, 24568867). These cases were scored with reduced points given the mild impact this variant has been shown to have on complex I function (PMID: 11935318). While three other missense variants (m.10543A>G, m.10591T>G, m.10680G>A) have been reported, this Expert Panel agreed there was only sufficient evidence of pathogenicity for the m.10663T>C variant (indeed, this variant is classified as likely pathogenic by the ClinGen Mitochondrial Disease Variant Curation Expert Panel). Cases with m.10680G>A (PMID: 29444077) and m.10543A>G and m.10591T>G (PMID: 17003408) were reviewed but excluded from scoring due to a lack of compelling functional evidence to support pathogenicity. The m.10543A>G variant has been modeled in E. coli and showed a very mild reduction in NADH dehydrogenase activity (74% of control; PMID: 35306226), which was not sufficient to be included in scoring.

This gene-disease association is also supported by its known biochemical function as a complex I subunit.

In summary, there is limited 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. Furthermore, this Gene Curation Expert Panel notes that, while variants in this gene have only been seen in those with LHON to date, additional cases and expansion of the phenotypic spectrum are likely to be seen in the future given the critical role of the ND4L subunit in complex I function. This classification was originally approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 20, 2022 (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.