NDUFS4

Inheritance Pattern: AR

Disease ID:MONDO:0100224

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFS4* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. The *NDUFS4* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S4, an iron-sulfur protein. Defects of this protein lead to complex I deficiency. *NDUFS4* was first reported in relation to autosomal recessive primary mitochondrial disease in 1998 (PMID: 9463323). While various names have been given to the constellation of features seen in those with *NDUFS4*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFS4* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFS4* was previously curated by this GCEP on February 11, 2019 (SOP Version 6) as having a definitive association with autosomal recessive Leigh syndrome spectrum (LSS). The scope of this current curation includes cases of primary mitochondrial disease, which includes LSS. Evidence supporting the relationship between *NDUFS4* and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes nine variants identified in 11 unrelated probands from ten publications (PMIDs: 9463323, 14765537, 12616398, 22326555, 24020637, 27079373, 27671926, 10944442, 11181577, 35379322). Nonsense, frameshift, splice, and missense variants have been reported. Affected individuals present with complex I deficiency and variable other features with a typically progressive disease course. Leigh syndrome spectrum disorders are the most common presentation; however, there is a report of adolescent-onset dystonia and parkinsonism (PMID: 29264396). Age of onset is typically in infancy or childhood. Clinical features may include LSS, lactic acidosis, developmental delay and regression, dystonia, ataxia, seizures, hypertrophic cardiomyopathy, bradycardia, respiratory insufficiency, respiratory failure, ophthalmoplegia, failure to thrive, and poor feeding. Complex I deficiency may be observed in muscle biopsy and/or cultured skin fibroblasts. The mechanism of disease is loss of function. This gene-disease association is also supported by a biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease as well as functional alteration in patient cells and model systems including Drosophila and mouse (PMIDs: 33340416, 14749350, 29590638, 18396137, 22653057). In summary, there is definitive evidence to support the relationship between *NDUFS4* 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 4, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0100224

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009640

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFS4 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 11, 2019. 18 articles were reviewed. NDUFS4 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1998 (Van den Heuvel et al 1998 PMID: 9463323). At least 12 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 probands with Leigh syndrome spectrum in 6 publications (PMID 27079373, 14765537, 27671926, 24020637, 22326555, 12616398). This gene-disease association is supported by protein interaction, expression, alterations in patient cell lines, and animal models. In summary, there is definitive evidence to support the relationship between NDUFS4 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 11, 2019 (SOP Version 6).