Submission Details

The relationship between NDUFA8 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 18, 2024. The NDUFA8 gene encodes NADH-ubiquinone oxidoreductase subunit A8, an accessory subunit of complex I that plays an important role in stabilizing enzyme assembly.

NDUFA8 was first reported in relation to autosomal recessive primary mitochondrial disease in 2020 (PMID: 32385911). Of note, there was a case reported in 2004 (PMID: 15576045) postulating digenic inheritance as an affected individual had a maternally inherited NDUFA8 missense variant and a paternally inherited NDUFS2 missense variant; however, no compelling evidence has emerged supporting this mechanism. While various names have been given to the constellation of features seen in those with NDUFA8-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFA8 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting the relationship between NDUFA8 and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes two homozygous missense variants identified in three individuals from two kindreds in two publications (PMIDs: 32385911, 33153867). Age of onset ranged from the first days to months of life to childhood. All reported cases are living. Two affected individuals from one family (PMID: 33153867) had a milder course. One individual had early-onset hypotonia, respiratory distress, status epilepticus/stroke-like episode, and lactic acidosis that generally resolved, as well as brain imaging showing multiple acute infarcts. The other sibling had bradycardia, hypotension and severe pulmonary hypertension with right ventricular dilation after anesthesia, with brain imaging showing mild bilateral cortical atrophy. Both had persistent language delay and mild failure to thrive. The other unrelated affected individual (PMID: 32385911) had a more severe phenotype including severe developmental delay, epilepsy, microcephaly, failure to thrive, with G-tube and respiratory support needed, and brain MRI showed cerebellar atrophy, cerebral atrophy, and thinning of corpus callosum. Muscle biopsies showed complex I deficiency and lab investigations showed elevated lactate, pyruvate, and alanine.

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, rescue, and model systems including knock-out mouse (PMIDs: 33340416, 33153867, 32385911, 27626380, 27626371).

In summary, there is moderate evidence to support the relationship between NDUFA8 and primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 18, 2024 (SOP Version 10).