NDUFB9 – Mitochondrial Complex I Deficiency

The association between NDUFB9 and mitochondrial complex I deficiency has limited clinical validity. In a cohort of 152 unrelated patients with complex I deficiency, a single individual harbored compound heterozygous variants in NDUFB9 (c.191T>C (p.Leu64Pro); c.294+5G>T), representing the first report of NDUFB9 as a disease gene (PMID:22200994). The absence of additional unrelated probands or segregation data beyond the index case constrains the strength of genetic evidence. Segregation in the family was not reported. However, a functional rescue assay in patient-derived fibroblasts demonstrated restoration of NDUFB9 protein and complex I activity upon expression of wild-type NDUFB9, confirming loss-of-function as the mechanism (PMID:22200994). This evidence supports a novel gene–disease link but falls short of achieving a definitive classification.

NDUFB9 variants follow autosomal recessive inheritance. The index case harbored compound heterozygous variants in NDUFB9: c.191T>C (p.Leu64Pro) and c.294+5G>T, both predicted to disrupt protein function (PMID:22200994). Functional complementation supports haploinsufficiency as the mechanism. There are no recurrent or founder variants described to date, and population frequency data remain unavailable. Additional genome-wide studies are required to identify further affected individuals and solidify penetrance estimates. Key take-away: NDUFB9 should be included in mitochondrial complex I deficiency gene panels, with functional assays essential for variant interpretation.

References

• Journal of medical genetics • 2012 • Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. PMID:22200994

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