Submission Details

The relationship between NDUFA1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of 2/28/2019. NDUFA1 was first reported in association with Leigh syndrome spectrum in 2007 (Fernandez-Moreira et al., PMID 17262856 ). Only three pathogenic variants in affected males (n=4, all inherited from unaffected mothers) predicted to cause a loss of function of the protein have been reported in ClinVar, suggesting hemizygous NDUFA1 loss of function resulting in Complex I deficiency is the disease mechanism for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PubMed: 17262856, 25356405, 28429146, 29506883) to reach a case-level evidence score of 5.5 pts. This gene-disease association is further supported by the function of the gene product, complex I alterations in patient cell lines, expression studies, and animal models reaching a maximal experimental score (6 points). In summary, NDUFA1 is definitively associated with X-linked recessive Leigh syndrome spectrum. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Although the total score was 11.5, the experts concluded that moderate level was more appropriate given the limited number of proven cases reported in the literature. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).