The relationship between NDUFAF2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 18, 2023. The NDUFAF2 gene (previously known as B17.2L and NDUFA12L) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 2. Defects of this protein lead to complex I deficiency.
NDUFAF2 was first reported in relation to autosomal recessive primary mitochondrial disease in 2005 (PMID: 16200211). While various names have been given to the constellation of features seen in those with NDUFAF2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFAF2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFAF2 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on November 23, 2020 (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 six variants (three unique nonsense variants, one start-loss variant, two frameshift variants expected to result in protein truncation) in four probands from four publications (PMIDs: 19384974, 20818383, 26795593, 37938061). Affected individuals had Leigh syndrome spectrum, progressive encephalopathy, and Leber Hereditary Optic Neuropathy. Complex I deficiency was noted in affected individuals in various tissues. 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, electron transport chain deficiencies in knockdown cell lines, and rescue studies in patient cells (PMIDs: 28797839, 23702311, 16200211).
In summary, there is definitive evidence to support the relationship between NDUFAF2 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 18, 2023 (SOP Version 10).
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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