NDUFS2 – Leigh syndrome

NDUFS2 (HGNC:7708) is implicated in autosomal recessive Leigh syndrome (MONDO:0009723) through biallelic loss-of-function and hypomorphic variants that impair mitochondrial complex I activity. This association is supported by multiple unrelated families and robust functional data. NDUFS2 | Leigh syndrome

Clinical Validity

A total of nine affected individuals from five unrelated families have been reported with pathogenic NDUFS2 variants, including a homozygous c.1336G>A (p.Asp446Asn) and compound heterozygous c.875T>C (p.Met292Thr) with c.866+4A>G founder alleles. Segregation analysis demonstrated co-segregation of biallelic variants with disease in four families (PMID:20819849, PMID:22036843). Based on replicated reports, segregation, and functional concordance, the gene–disease association is classified as Strong.

Genetic Evidence

Inheritance is autosomal recessive. Four unrelated probands harbored compound heterozygous or homozygous NDUFS2 variants, with a recurrent c.875T>C (p.Met292Thr) variant observed in three Caucasian children and a splice variant c.866+4A>G indicating a founder effect (PMID:20819849). An additional homozygous c.1336G>A (p.Asp446Asn) variant was identified in a fifth patient. Segregation of these variants with disease in four families establishes strong genetic evidence under ClinGen criteria.

Functional Evidence

Fibroblasts from the patient with p.Asp446Asn exhibited normal complex I assembly but a >90% reduction in enzymatic activity, which was fully rescued by wild-type NDUFS2 transduction (PMID:22036843). Structural modelling localizes Asp446 near the coenzyme Q binding site, supporting a mechanism of impaired quinone reduction and proton pumping. These assays provide moderate functional support.

Conflicting Evidence

No studies to date have refuted the role of NDUFS2 variants in Leigh syndrome or reported alternative phenotypes for these specific alleles.

Conclusion

Genetic and experimental data cumulatively support a Strong clinical validity for NDUFS2 in autosomal recessive Leigh syndrome. Key take-home: diagnostic testing of NDUFS2 informs clinical management and genetic counselling for Leigh syndrome.

References

• Brain • 2010 • The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. PMID:20819849
• Biochimica et biophysica acta • 2012 • A catalytic defect in mitochondrial respiratory chain complex I due to a mutation in NDUFS2 in a patient with Leigh syndrome. PMID:22036843

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