Submission Details

The relationship between NDUFS4 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. The NDUFS4 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S4, an iron-sulfur protein. Defects of this protein lead to complex I deficiency.

NDUFS4 was first reported in relation to autosomal recessive primary mitochondrial disease in 1998 (PMID: 9463323). While various names have been given to the constellation of features seen in those with NDUFS4-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS4 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFS4 was previously curated by this GCEP on February 11, 2019 (SOP Version 6) as having a definitive association with autosomal recessive Leigh syndrome spectrum (LSS). The scope of this current curation includes cases of primary mitochondrial disease, which includes LSS.

Evidence supporting the relationship between NDUFS4 and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes nine variants identified in 11 unrelated probands from ten publications (PMIDs: 9463323, 14765537, 12616398, 22326555, 24020637, 27079373, 27671926, 10944442, 11181577, 35379322). Nonsense, frameshift, splice, and missense variants have been reported. Affected individuals present with complex I deficiency and variable other features with a typically progressive disease course. Leigh syndrome spectrum disorders are the most common presentation; however, there is a report of adolescent-onset dystonia and parkinsonism (PMID: 29264396). Age of onset is typically in infancy or childhood. Clinical features may include LSS, lactic acidosis, developmental delay and regression, dystonia, ataxia, seizures, hypertrophic cardiomyopathy, bradycardia, respiratory insufficiency, respiratory failure, ophthalmoplegia, failure to thrive, and poor feeding. Complex I deficiency may be observed in muscle biopsy and/or cultured skin fibroblasts.

The mechanism of disease is loss of function. This gene-disease association is also supported by a biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease as well as functional alteration in patient cells and model systems including Drosophila and mouse (PMIDs: 33340416, 14749350, 29590638, 18396137, 22653057).

In summary, there is definitive evidence to support the relationship between NDUFS4 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 4, 2023 (SOP Version 9).