Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Pathogenic variants in the nuclear gene NDUFAF8 are associated with mitochondrial complex I deficiency, a condition that can manifest as Leigh syndrome. To date, only three unrelated probands have been described, each presenting with biochemical evidence of complex I dysfunction and a clinical phenotype consistent with Leigh syndrome (PMID:39921456).
The genetic evidence supporting this association is derived primarily from case reports and multi‐patient studies. Although segregation data in extended families is limited, the consistent identification of NDUFAF8 variants among affected individuals adds weight to the gene-disease correlation (PMID:39921456).
Inheritance of the condition appears to follow an autosomal recessive pattern, which is typical for mitochondrial complex I deficiency. In this context, both alleles of NDUFAF8 need to be mutated to disrupt the critical role of the gene product in complex I assembly and function.
Although specific variant details were not extensively catalogued in the provided evidence, the overall variant spectrum supports a loss-of-function mechanism. The biochemical defect observed in these patients is consistent with disrupted complex I assembly, a finding that aligns with the clinical presentations of Leigh syndrome and premature death.
Functional assessment studies, albeit limited in number, have demonstrated that NDUFAF8 deficiency impairs the assembly of complex I. These experimental results not only corroborate the clinical and genetic findings but also suggest a direct pathogenic mechanism through loss-of-function effects (PMID:39921456).
In summary, despite the small number of cases, the convergence of clinical, genetic, and functional evidence supports the association between NDUFAF8 and mitochondrial complex I deficiency. This association, while currently limited by case number, provides a clinically useful insight that underscores the importance of exhaustive genomic evaluation in patients with Leigh syndrome.
Gene–Disease AssociationLimitedThree unrelated probands (PMID:39921456) exhibit a consistent mitochondrial complex I deficiency and Leigh syndrome phenotype. Genetic EvidenceLimitedThe cases provide compelling clinical and biochemical evidence; however, segregation data is minimal and the total number of probands remains low (PMID:39921456). Functional EvidenceModerateFunctional studies demonstrate impaired complex I assembly in patient-derived models, supporting a loss-of-function mechanism (PMID:39921456). |