NDUFAF4

Inheritance Pattern: AR

Disease ID:MONDO:0032620

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFAF4* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 6, 2023. The *NDUFAF4* gene (previously known as *C6ORF66*) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 4. Defects of this protein lead to complex I deficiency. The *NDUFAF4* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18179882). While various names have been given to the constellation of features seen in those with *NDUFAF4*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFAF4* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFAF4* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on February 12, 2020 (SOP v7), with a final classification of Limited. This current curation for the association with primary mitochondrial disease includes the single case included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four variants in four cases from four publications (PMIDs: 18179882, 30369941, 28853723, 32949790), as well as segregation data from the first large family reported (PMID: 18179882). Affected individuals typically presented in the neonatal period with severe lactic acidosis leading to neonatal mortality or severe neurological involvement for surviving children. Additional features include intrauterine growth restriction, lactic acidosis, LSS disorder, encephalopathy, seizures, dystonia, limited spontaneous movements, myopathy, hypertrophic cardiomyopathy, sensorineural hearing loss, optic atrophy, and failure to thrive. Complex I deficiency is noted in muscle and/or skin fibroblasts. 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 functional alteration in patient cells (PMIDs: 18179882, 33340416). 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 September 6, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFAF4 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 13, 2020. The NDUFAF4 gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 4. The NDUFAF4 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2017 (PMID: 28853723). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 28853723). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, and rescue in patient cells (PMIDs: 18179882, 25613900, 23670274). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 13, 2020 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0032620

Submitter: Labcorp Genetics (formerly Invitae)