TY - JOUR T1 - Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes <em>SDHB</em>, <em>SDHC</em> and <em>SDHD</em> JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2017-105127 SP - jmedgenet-2017-105127 AU - Katrina A Andrews AU - David B Ascher AU - Douglas Eduardo Valente Pires AU - Daniel R Barnes AU - Lindsey Vialard AU - Ruth T Casey AU - Nicola Bradshaw AU - Julian Adlard AU - Simon Aylwin AU - Paul Brennan AU - Carole Brewer AU - Trevor Cole AU - Jackie A Cook AU - Rosemarie Davidson AU - Alan Donaldson AU - Alan Fryer AU - Lynn Greenhalgh AU - Shirley V hodgson AU - Richard Irving AU - Fiona Lalloo AU - Michelle McConachie AU - Vivienne P M McConnell AU - Patrick J Morrison AU - Victoria Murday AU - Soo-Mi Park AU - Helen L Simpson AU - Katie Snape AU - Susan Stewart AU - Susan E Tomkins AU - Yvonne Wallis AU - Louise Izatt AU - David Goudie AU - Robert S Lindsay AU - Colin G Perry AU - Emma R Woodward AU - Antonis C Antoniou AU - Eamonn R Maher Y1 - 2018/01/31 UR - http://jmg.bmj.com/content/early/2018/01/31/jmedgenet-2017-105127.abstract N2 - Background Germline pathogenic variants in SDHB/SDHC/SDHD 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 SDHB/SDHC/SDHD mutation carriers.Methods 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 SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.Results 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 SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD 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 SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB 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%).Conclusions Overall risks of clinically apparent tumours for SDHB 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 SDHB/SDHC/SDHD mutation carriers. ER -