Submission Details

The relationship between NDUFAF5 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 18, 2024. The NDUFAF5 gene (previously known as C20orf7) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 5, an arginine hydroxylase involved in the assembly of complex I. Defects of this protein lead to complex I deficiency.

NDUFAF5 was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18940309). While various names have been given to the constellation of features seen in those with NDUFAF5-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFAF5 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFAF5 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on February 3, 2021 (SOP v7), with a final classification of Definitive. The scope of this current curation encompassed cases of primary mitochondrial disease, which includes cases with LSS.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 variants (eight unique missense variants including an Ashkenazi founder variant c.749G>T; p.Gly250Val; ClinVar Variation ID: 372253; two intronic variants, and a four-nucleotide deletion expected to result in protein truncation) in 11 probands from eight publications (PMIDs: 18940309, 19542079, 21607760, 29581464, 34797029, 36580434, 30473481). The condition was first described in a patient with neonatal lactic acidosis and agenesis of the corpus callosum who died of cardiopulmonary arrest. Subsequent reported patients also had Leigh syndrome, optic atrophy, and myopathy, and some individuals had clinical features consistent with Leber Hereditary Optic Neuropathy and intellectual disability (PMIDs: 19542079, 21607760, 29581464, 34797029, 36580434, 30473481). Additional cases are reported in the literature, but maximum case scoring was reached.

The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease, expression of NDUFAF5 in brain tissue, and model studies in Dictyostelium and in MCH58 Cells (PMIDs: 28797839, 25613900, 23536703, 18940309).

In summary, there is definitive evidence to support the relationship between NDUFAF5 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 January 18, 2024 (SOP Version 10).