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Mitochondrial complex I deficiency is an autosomal recessive disorder characterized by impaired assembly of NADH:ubiquinone oxidoreductase leading to variable phenotypes, including fatal infantile hypertrophic cardiomyopathy. In a cohort of 30 pediatric patients with isolated complex I deficiency, sequence analysis of NDUFAF1 revealed compound heterozygous missense variants c.631C>T (p.Arg211Cys) and c.733G>A (p.Gly245Arg) in one patient with fatal infantile hypertrophic cardiomyopathy; these variants were absent in 240 ethnically matched control alleles (PMID:21931170). No additional NDUFAF1 mutations were identified in the remaining 29 patients (PMID:21931170).
Functional assays in patient fibroblasts demonstrated a severe reduction of NDUFAF1 protein on Western blot and accumulation of abnormal complex I assembly intermediates on Blue Native PAGE, confirming a loss-of-function mechanism consistent with misassembly of complex I (PMID:21931170). These data provide preliminary evidence for NDUFAF1 deficiency as a cause of infantile hypertrophic cardiomyopathy, warranting inclusion of NDUFAF1 in diagnostic panels for complex I–related mitochondrial disease.
Gene–Disease AssociationLimitedSingle unrelated proband with compound heterozygous NDUFAF1 missense variants and supporting functional data Genetic EvidenceLimited2 missense variants in one proband; autosomal recessive inheritance; absent from 240 controls (PMID:21931170) Functional EvidenceModeratePatient fibroblast studies show severe NDUFAF1 depletion and complex I assembly intermediates accumulation (PMID:21931170) |