NDUFA1

Inheritance Pattern: AR

Disease ID:MONDO:0026720

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0026720

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0026720

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFA1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of 2/28/2019. NDUFA1 was first reported in association with Leigh syndrome spectrum in 2007 (Fernandez-Moreira et al., PMID 17262856 ). Only three pathogenic variants in affected males (n=4, all inherited from unaffected mothers) predicted to cause a loss of function of the protein have been reported in ClinVar, suggesting hemizygous NDUFA1 loss of function resulting in Complex I deficiency is the disease mechanism for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PubMed: 17262856, 25356405, 28429146, 29506883) to reach a case-level evidence score of 5.5 pts. This gene-disease association is further supported by the function of the gene product, complex I alterations in patient cell lines, expression studies, and animal models reaching a maximal experimental score (6 points). In summary, NDUFA1 is definitively associated with X-linked recessive Leigh syndrome spectrum. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Although the total score was 11.5, the experts concluded that moderate level was more appropriate given the limited number of proven cases reported in the literature. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).

Inheritance Pattern: XL

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA1* and *NDUFA1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 18, 2024. The *NDUFA1* gene encodes NADH:ubiquinone oxidoreductase (complex I) subunit A1. Defects of this protein lead to complex I deficiency. The *NDUFA1* gene was first reported in relation to X-linked *NDUFA1*-related primary mitochondrial disease in 2007 (PMID: 17262856). *NDUFA1* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 12 [OMIM# 301020]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFA1*-related primary mitochondrial disease. Of note, *NDUFA1* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on March 25, 2019 (SOP v6), with a final classification of Moderate. This current curation for the association with *NDUFA1*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique missense variants identified in four unrelated cases from three publications (PMIDs: 17262856, 25356405, 29506883; additional details provided in PMIDs: 20153825, 28429146). Age of onset was the first year of life for all reported cases. Outcomes were variable and ranged from death at age 14 months to alive at age 10 years. All four cases had LSS. Complex I deficiency was noted on muscle biopsy and blood lactate levels were normal to elevated. Additional cases have been reported but were excluded from this curation given lack of clinical and variant details (PMID: 25356970), or high variant allele frequency (PMIDs: 21596602, 29353736, 29272804, 19185523, 35131137). 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 HEK293T cells, and model systems including Chinese hamster cell line (PMIDs: 10200266, 14722084, 15576048) and mouse model (PMIDs: 15293270, 12557286, 28506826). In summary, there is moderate evidence to support the relationship between *NDUFA1* and X-linked *NDUFA1*-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 November 18, 2024 (SOP Version 10).

Inheritance Pattern: XL

Disease ID:MONDO:0026720

Submitter: Labcorp Genetics (formerly Invitae)