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NDUFA6 encodes a 15 kDa LYR-motif-containing structural subunit of respiratory complex I. Early-onset isolated complex I deficiency manifests clinically with neurodevelopmental delay, elevated lactate, and characteristic neuroradiological findings. Four unrelated children presenting with these features were found to harbor bi-allelic NDUFA6 variants, establishing a novel gene-disease link (PMID:30245030).
Genetic analyses across these four families revealed seven distinct variants in NDUFA6: four frameshift indels (c.281_284del (p.Ile94fs), c.355del (p.Leu119fs), c.331_332del (p.Glu111fs), c.309del (p.Met104fs)), one nonsense (c.265G>T (p.Glu89Ter)), one missense (c.191G>C (p.Arg64Pro)), and one start-loss (c.3G>A (p.Met1Ile)). All variants segregated in an autosomal recessive pattern with affected probands in unrelated families, consistent with loss-of-function mechanism.
Functional studies in patient fibroblast cell lines demonstrated severe complex I assembly defects by mass-spectrometry-based complexome profiling, showing markedly reduced incorporation of NDUFA6 and other Q-module subunits. Lentiviral transduction of wild-type NDUFA6 rescued complex I assembly and activity, confirming variant pathogenicity (PMID:30245030).
The mechanism of disease is loss of function of NDUFA6 leading to deficient assembly of the Q-module and impaired supercomplex formation. No conflicting evidence has been reported to date.
Based on four unrelated probands with bi-allelic pathogenic variants and robust functional rescue studies, the clinical validity of the NDUFA6–mitochondrial complex I deficiency association is classified as Strong. Genetic evidence reaches ClinGen strong criteria with multiple variant types in independent families. Functional evidence is rated Moderate due to concordant cellular assays with rescue.
Key take-home: NDUFA6 loss-of-function underlies early-onset isolated complex I deficiency, enabling precise molecular diagnosis and informing potential gene-based therapies.
Gene–Disease AssociationStrong4 unrelated probands with bi-allelic NDUFA6 variants and concordant functional rescue ([PMID:30245030]) Genetic EvidenceStrongSeven distinct LoF and missense variants identified in 4 independent families under AR inheritance Functional EvidenceModerateComplexome profiling in patient fibroblasts shows assembly defect and lentiviral rescue normalizes complex I ([PMID:30245030]) |