NDUFC2 – Leigh Syndrome

NDUFC2 has been robustly associated with early-onset Leigh syndrome, a progressive neurodegenerative disorder primarily manifesting in childhood. Multiple lines of evidence support this gene-disease relationship, including case reports documenting bi-allelic pathogenic variants in affected children and in-depth biochemical analyses demonstrating impaired assembly of mitochondrial complex I, which is consistent with the clinical hallmarks of Leigh syndrome such as developmental regression and characteristic neuroimaging findings (PMID:32969598, PMID:24731534).

The genetic evidence is reinforced by the identification of two distinct homozygous variants in NDUFC2. In one key study, three affected children from two unrelated families were found to harbor the variant c.173A>T (p.His58Leu). This finding is further supported by segregation analyses within these families and confirmed in broader multi-patient cohorts, providing a strong genetic basis for the association (PMID:32969598).

Functionally, studies have demonstrated that pathogenic NDUFC2 variants result in severely reduced complex I activity, disrupted subunit expression, and impaired holoenzyme assembly. Rescue experiments in patient fibroblasts using wild-type NDUFC2 cDNA have resulted in improved complex I assembly, thereby corroborating the pathogenic role of these variants. Additional in vitro studies have shown that NDUFC2 deficiency leads to marked mitochondrial dysfunction and structural deficiencies, offering further mechanistic insight (PMID:28973657).

Collectively, the synthesis of genetic and experimental data strongly supports the role of NDUFC2 deficiency in the pathogenesis of Leigh syndrome. Although additional studies have explored the impact of NDUFC2 in other conditions, there is no conflicting evidence that undermines its established pathogenicity in the context of mitochondrial complex I deficiency associated with Leigh syndrome.

This integrated evaluation meets and exceeds ClinGen scoring thresholds due to the consistent replication of findings across independent cohorts and functional studies, making the NDUFC2–Leigh syndrome association highly reliable for clinical diagnostic decision‑making, commercial applications, and future research publication.

Key take‑home sentence: The converging genetic and functional evidence validates NDUFC2 as a clinically actionable gene in the diagnosis and management of early-onset Leigh syndrome.

References

• EMBO molecular medicine • 2020 • Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I PMID:32969598
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• Human molecular genetics • 2017 • In vitro characterization of mitochondrial function and structure in rat and human cells with a deficiency of the NADH: ubiquinone oxidoreductase Ndufc2 subunit PMID:28973657

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