Likely inborn error of metabolism

Gene: NDUFA5

Green List (high evidence)

Comment on list classification: There are five patients from four unrelated families reported with complex I deficiency and biallelic NDUFA5 variants. There is also functional evidence available from in vitro studies and animal models. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 14 Apr 2026, 3:54 p.m. | Last Modified: 14 Apr 2026, 3:54 p.m.

Panel Version: 8.110

PMID:41859003 (2025) reported a 4-month old male patient presenting with respiratory infection, dyspnea, altered mental status, seizures, and shock. In addition, the patient also displayed delayed development after birth. Compound heterozygous variants in NDUFA5 gene were identified via whole genome sequencing and confirmed with Sanger sequencing in this patient. There is also in vitro functional evidence available for these variants, which demonstrated their pathogenicity.

PMID:41916321 (2026) reported four individuals from three unrelated families with biallelic NDUFA5 variants (compound heterozygous in two families and homozygous in one family). They all presented with a variable multisystem disease in the setting of a mitochondrial complex I deficiency and encompassing severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome. It was also biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Zebrafish ndufa5 F0 mutants also exhibited defects of morphological development, locomotor deficits, and abnormal brain activity.

This gene has not yet been associated with relevant phenotypes either in OMIM (last accessed 14 April 2026) or in Gene2Phenotype.

Created: 14 Apr 2026, 3:51 p.m. | Last Modified: 14 Apr 2026, 3:51 p.m.

Panel Version: 8.107

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mitochondrial complex I deficiency, MONDO:0100133

Publications

• 41859003
• 41916321

I don't know

no mutation reports in literature; good candidate gene for complex I deficiency (encodes a subunit of the enzyme)

Created: 4 Feb 2016, 7:02 p.m.