Tumour risks and genotype–phenotype–proteotype analysis of patients with germline mutations in the succinate dehydrogenase subunit genes SDHB, SDHC , and SDHD

Abstract Background Germline mutations in the succinate dehydrogenase subunit genes SDHB, SDHC , and SDHD are the most frequent causes of inherited phaeochromocytomas and paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. Our aim was to provide estimates of penetrance and genotype–phenotype correlations in a large cohort of succinate dehydrogenase mutation carriers. Methods We undertook a retrospective survey of 800 individuals in the UK (401 previously reported) with germline mutations in SDHB (620), SDHC (31), and SDHD (149). We estimated and compared tumour risks for each gene according to age using survival analysis and Cox proportional hazards modelling with the statistical programming language R. DUET, a computational approach for predicting the effects of mutations on protein stability, was used to evaluate the functional effects of SDHB and SDHD mutations. Findings Analysis of age-related tumour risks provided novel estimates of penetrance. In addition to tumour-specific differences in risk for individual genes, we confirmed that the SDHD p.Pro81Leu mutation had a distinct phenotype, with a low risk of phaeochromocytoma and extra-adrenal paraganglioma (only one case in 55 patients), and found evidence suggesting higher penetrance with SDHB p.Ile127Ser mutations. Comparison of age-dependent penetrance of disease in p.Ile127Ser carriers versus other SDHB missense mutation carriers showed that p.Ile127Ser was associated with a higher overall penetrance of phaeochromocytoma and paraganglioma (χ2 =4·49, p=0·034). SDHB p.Ile127Ser was predicted by DUET to be the most destabilising SDHB missense mutation, through disruption of key intramolecular hydrophobic interactions by the introduction of a polar serine. The penetrance in SDHB and SDHD mutation-positive non-probands by age 60 years was 22·1% (95% CI 15·6–28·3) and 47·5% (29·3–61·1), respectively, and the risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4·2% (1·1–7·2). Interpretation Increased knowledge of the lifetime tumour risks is crucial to long-term surveillance and management. Knowledge of the molecular basis of the phenotypic variability commonly observed in individuals with germline SDHB, SDHC , and SDHD mutations will facilitate the development of personalised management based on gene-specific and mutation-specific tumour risks. Funding East Anglian Foundation Programme (K