Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma.

BACKGROUND

Pathogenic germline variants in subunits of succinate dehydrogenase (, and ) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.

METHODS

Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the , or genes.

RESULTS

Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence truncating, missense, truncating and missense, with the opposite pattern apparent for HNPGL (p<0.001).

CONCLUSIONS

truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to . We propose that surveillance and counselling of carriers of should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.