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Mitochondrial complex I deficiency is the most prevalent OXPHOS defect characterized by infantile-onset encephalopathy and brainstem degeneration. Biallelic pathogenic variants in NDUFAF2, encoding a nuclear assembly factor for complex I, have been implicated in an autosomal recessive form of this disorder. To date, 14 unrelated probands from consanguineous and outbred populations have been reported with NDUFAF2-associated complex I deficiency (PMID:19384974; PMID:38419071). These individuals display infantile-onset growth retardation, ophthalmological impairments with nystagmus and strabismus, progressive respiratory insufficiency with apnea, and developmental regression. Enzymatic assays consistently demonstrate severely reduced complex I activity in patient-derived fibroblasts and muscle biopsies. The cumulative genetic and epidemiological data support a strong gene–disease relationship.
All reported cases follow an autosomal recessive inheritance mode with homozygous or compound heterozygous loss-of-function variants; segregation analyses confirm biallelic transmission in consanguineous pedigrees ([PMID:19384974]; [PMID:39621529]). The variant spectrum comprises five distinct LoF alleles: c.9G>A (p.Trp3Ter), c.1A>T (p.Met1Leu), c.114C>G (p.Tyr38Ter), c.221G>A (p.Trp74Ter), and c.103del (p.Ile35SerfsTer18) ([PMID:38419071]). The recurrent c.114C>G (p.Tyr38Ter) truncates the protein at residue 38 and was first identified by homozygosity mapping in a consanguineous family ([PMID:19384974]). Population databases show these variants are absent or extremely rare, with no evidence of founder effects.
Functional studies demonstrate that c.114C>G (p.Tyr38Ter) severely disrupts complex I assembly and activity in patient fibroblasts, which is almost completely rescued by baculovirus-mediated complementation with wild-type NDUFAF2 ([PMID:19384974]). In vitro knockout models in human neuroblastoma cells and primary fibroblasts from Ndufaf2-null mice reproduce selective reduction of complex I activity, increased oxidative stress, and mitochondrial DNA deletions without accumulation of assembly intermediates ([PMID:23702311]). Western blot analyses in patient fibroblasts and mouse tissues confirm absence or marked reduction of NDUFAF2 protein levels ([PMID:38419071]). These data indicate a loss-of-function mechanism consistent with an essential chaperone role for NDUFAF2.
Animal models and cellular assays reveal that NDUFAF2, while not required for the assembly of mature complex I, acts as a critical chaperone for proper folding and stability, linking complex I dysfunction to oxidative stress pathways ([PMID:23702311]). Brainstem neurodegeneration and early lethality observed in knockout models recapitulate key clinical features of affected patients. To date, no studies have presented conflicting evidence or alternative phenotypic assignments for NDUFAF2 variants in this context.
Overall, the integration of genetic segregation across multiple families, a consistent spectrum of biallelic loss-of-function variants, concordant functional rescue experiments, and relevant animal models supports a Strong clinical validity classification. Genetic evidence meets the ClinGen Strong tier with 14 probands harboring pathogenic variants. Functional evidence is graded Moderate due to robust in vitro and in vivo studies demonstrating rescue and phenocopy.
Key take-home: Incorporating NDUFAF2 into diagnostic gene panels for autosomal recessive mitochondrial complex I deficiency will enhance molecular diagnosis and inform clinical management.
Gene–Disease AssociationStrong14 probands, multi-family segregation, concordant functional data Genetic EvidenceStrong14 unrelated probands with biallelic loss-of-function variants reaching ClinGen genetic cap Functional EvidenceModerateRescue experiments, knockout models display CI deficiency and oxidative stress |