Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes <i>SDHB</i>, <i>SDHC</i> and <i>SDHD</i>.

Abstract

Germline pathogenic variants in <i>SDHB/SDHC</i>/<i>SDHD</i> are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of <i>SDHB/SDHC</i>/<i>SDHD</i> mutation carriers. A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in <i>SDHB/SDHC</i>/<i>SDHD</i> (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the <i>SDHD:</i>p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising <i>SDHB</i> missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in <i>SDHB</i> and (paternally inherited) <i>SDHD</i> mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband <i>SDHB</i> mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for <i>SDHB</i> mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). Overall risks of clinically apparent tumours for <i>SDHB</i> mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for <i>SDHB/SDHC</i>/<i>SDHD</i> mutation carriers.