Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.

Loss-of-function of a structural subunit of the peripheral arm of mitochondrial complex I (NADH:ubiquinone oxidoreductase)

NDUFA5, encoding a structural subunit of the peripheral arm of mitochondrial complex I, is reported as a novel Mendelian disease gene. Four individuals from three unrelated families with bi-allelic NDUFA5 variants presented with variable multisystem disease: severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome. Complex I deficiency was confirmed by respiratory chain enzymology, blue native PAGE, and mass spectrometry-based proteomics across multiple cell types. Transcriptomics revealed aberrant mRNA expression, and zebrafish ndufa5 knockouts recapitulated developmental and neurological defects.

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Despite the small cohort (four individuals from three families), evidence is robust through multi-omics validation and zebrafish modeling. Phenotypic heterogeneity — from severe congenital heart disease to Leigh syndrome — mirrors other complex I subunit deficiencies. NDUFA5 should be added to mitochondrial disease gene panels without delay.

Clinical impact : 2/3 · Evidence strength : 2/3 · Novelty : 2/2 · Sample size : 0/1 · Journal quality : 1/1 → Total : 7/10