NDUFS3

Inheritance Pattern: AR

Disease ID:MONDO:0032613

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFS3* and *NDUFS3*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 19, 2024. The *NDUFS3* gene encodes a complex I subunit from the iron-sulfur protein fraction of complex I. The *NDUFS3* gene was first reported in relation to autosomal recessive *NDUFS3*-related primary mitochondrial disease in 2004 (PMID: 14729820). *NDUFS3* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 8 [OMIM# 618230]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFS3*-related primary mitochondrial disease. Of note, *NDUFS3* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on June 10, 2019 (SOP v6), with a final classification of Moderate. This current curation for the association with *NDUFS3*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (four missense, one intronic variant shown to impact splicing) identified in four unrelated cases from four publications (PMIDs: 14729820, 22499348, 30140060, 33097395). Additional cases are reported in the literature, but did not meet criteria to be included in scoring (PMIDs: 36531773, 19167255). Age of onset is childhood. Clinical features in affected individuals include LSS, encephalomyopathy, developmental delay and regression, ataxia, dystonia, optic atrophy, pancreatitis, respiratory insufficiency, and lactic acidosis. Complex I deficiency is seen in muscle biopsy. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in non-patient cells (PMID: 30796225), and a conditional knockout mouse model (PMID: 33148885) with subsequent studies showing rescue of the phenotype with AAV vector-based gene replacement of NDUFS3 (PMID: 39169163). In summary, there is moderate evidence to support the relationship between *NDUFS3* and autosomal recessive *NDUFS3*-related primary mitochondrial disease. 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 19, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFS3 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 12, 2019. NDUFS3 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2004 (Benit et al., PMID 14729820). Several variants 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 14729820, 22200994) to reach a case-level evidence score of 3.5 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 5.5 points. The mechanism for disease is complex I deficiency. In summary, NDUFS3 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 June 10, 2019 (SOP Version 6).

Inheritance Pattern: AR

Disease ID:MONDO:0032613

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet