NDUFA2

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0032618

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013058

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032618

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFA2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 14, 2019. NDUFA2 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2008 (Hoefs et al., PMID 18513682). Several variants in the NDUFA2 gene have been reported in ClinVar, but mostly with limited evidence of pathogenicity. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PMIDs 18513682, 28857146, 27159321) to reach a case-level evidence score of 4.5 points. This gene-disease association is further supported by the function of the gene product, complex I alterations in cell lines, expression studies, and animal models reaching an experimental score of 5.0 points. The mechanism for disease is complex I deficiency. In summary, NDUFA2 is moderately associated with autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).