Functional Characterization of SDHB Variants Clarifies Hereditary Pheochromocytoma and Paraganglioma Risk and Genotype-Phenotype Relationships.

Summary

Using a succinate/fumarate ratio–based cellular complementation assay, the authors functionally classified SDHB missense variants with high accuracy, enabling reclassification of 87% of tested VUS. The work establishes domain-specific functional effects, links hypomorphic variants to head and neck paragangliomas, and delivers immediately actionable evidence for clinical genetics in hPPGL.

Key Findings

• A cellular complementation assay quantifying intracellular succinate/fumarate reliably separated pathogenic from benign SDHB alleles.
• Functional testing supported reclassification of 87% of patient-derived SDHB VUS.
• Iron–sulfur cluster domain variants were amorphic, whereas variants at/after Tyr273 retained function.
• Hypomorphic SDHB variants correlated with increased head and neck paraganglioma prevalence, establishing a genotype–phenotype link.
• Leigh syndrome–associated SDHB variants retained activity, consistent with distinct biallelic disease mechanisms.

Clinical Implications

Clinicians can use functionally validated SDHB classifications to tailor surveillance intensity, guide cascade testing, and refine surgical and imaging plans for hPPGL families.

Limitations

• Exact number and spectrum of tested variants are not detailed in the abstract
• Clinical reclassification impact needs prospective validation in diverse cohorts

Future Directions

Prospective integration of the assay into clinical pipelines for SDHB variant interpretation, expansion to other SDHx genes, and correlation with penetrance and outcomes.