Germline Pathogenic Variants in Succinate Dehydrogenase Genes: Implications from a Single Institution Study

Germline pathogenic variants (PVs) in the succinate dehydrogenase (SDHx) genes are associated with inherited pheochromocytoma-paraganglioma (PPGL). Because of the high incidence of germline PVs, genetic testing is recommended for all cases of PPGL; relatives may thus be found through cascade testing. PPGL-associated genes are also included on cancer genetics panels, which may lead to variant identification related to other tumors. After PV detection, screening recommendations entail biochemical/radiologic testing and frequent surveillance.

To assess the consequences and impact of these approaches in a cohort of individuals with germline PVs in the SDHx genes.

Natural history study.

Single academic medical centerPatients or Other Participants: 156 patients with SDHx PVs collected over 10 years.

None.

We report distribution of PVs; rationale for genetic screening; tumor incidence, and second genetic variants.

Of 156 patients with variants in the SDHx genes, PVs in SDHB were the most common. In probands tested for non-PPGL tumors, SDHA PVs were the most common, whereas SDHD cases were never detected in this manner. We also identified individuals with variants in a second cancer-associated gene. For individuals not found to have a tumor at initial presentation, the rate of tumor development was <5%.

SDHx PVs may be more common than expected and there are gene-specific patterns of ascertainment. Future research is needed to evaluate the role of modifier variants on tumor risk. Reconsideration of surveillance guidelines may be appropriate given the low frequency of new lesions in tumor-free carriers.