The relationship between NDUFAF3 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The NDUFAF3 gene (previously known as C3ORF60) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 3. Defects of this protein lead to complex I deficiency.
The NDUFAF3 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19463981), in three unrelated families with severe neonatal lactic acidosis. While various names have been given to the constellation of features seen in those with NDUFAF3-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFAF3 phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants (four missense, one initiation codon, one in-frame duplication) in five cases from three publications (PMIDs: 19463981, 27986404, 29344937). Affected individuals typically presented in the neonatal period to early childhood and clinical features include Leigh syndrome spectrum (LSS), neonatal lactic acidosis, developmental regression, hypotonia, myoclonic seizures, and optic atrophy. Respiratory chain enzyme activity assays in muscle and fibroblasts revealed complex I deficiency. Loss of function resulting in a complex I assembly defect is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and model systems in Caenorhabditis elegans and Drosophila melanogaster (PMIDs: 27509854, 22387847, 34386730).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. 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 March 7, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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