The relationship between NDUFA2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 7, 2023. The NDUFA2 gene encodes the NADH dehydrogenase 1 alpha subcomplex subunit 2 protein, which is an accessory subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency.
NDUFA2 was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18513682). While various names could be given to the constellation of features seen in those with NDUFA2-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFA2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFA2 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on March 13, 2019 (SOP v6), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes cases with LSS.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes four variants in four probands across four publications (PMIDs: 18513682; 27159321; 28857146; 32154054). Affected individuals had a fairly consistent phenotype with early childhood onset and including Leigh syndrome spectrum, global developmental delay and/or regression, spasticity, upper motor neuron signs, microcephaly, seizures, hypertrophic cardiomyopathy, and failure to thrive; with brain imaging findings including cerebral atrophy, hypoplasia of the corpus callosum, and demyelination. Lab abnormalities include lactic acidemia, hypoketotic hypoglycemia, and/or hyperammonemia. Complex I deficiency was noted in muscle and/or fibroblasts.
Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function, functional alteration in patient cells, a cell culture model, and transgenic rescue in model systems (PMID: 18513682; 22822087; 27626371; 33340416).
In summary, there is moderate evidence to support the relationship between NDUFA2 and autosomal recessive primary mitochondrial disease. However, given the consistent clinical and biochemical phenotype seen in the four reported cases, this Expert Panel elected to upgrade the classification to Definitive. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 7, 2023 (SOP Version 9).
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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