@article {Andrewsjmedgenet-2017-105127, author = {Katrina A Andrews and David B Ascher and Douglas Eduardo Valente Pires and Daniel R Barnes and Lindsey Vialard and Ruth T Casey and Nicola Bradshaw and Julian Adlard and Simon Aylwin and Paul Brennan and Carole Brewer and Trevor Cole and Jackie A Cook and Rosemarie Davidson and Alan Donaldson and Alan Fryer and Lynn Greenhalgh and Shirley V hodgson and Richard Irving and Fiona Lalloo and Michelle McConachie and Vivienne P M McConnell and Patrick J Morrison and Victoria Murday and Soo-Mi Park and Helen L Simpson and Katie Snape and Susan Stewart and Susan E Tomkins and Yvonne Wallis and Louise Izatt and David Goudie and Robert S Lindsay and Colin G Perry and Emma R Woodward and Antonis C Antoniou and Eamonn R Maher}, title = {Tumour risks and genotype{\textendash}phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD}, elocation-id = {jmedgenet-2017-105127}, year = {2018}, doi = {10.1136/jmedgenet-2017-105127}, publisher = {BMJ Publishing Group Ltd}, abstract = {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{\textendash}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{\textendash}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{\textendash}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.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/early/2018/01/31/jmedgenet-2017-105127}, eprint = {https://jmg.bmj.com/content/early/2018/01/31/jmedgenet-2017-105127.full.pdf}, journal = {Journal of Medical Genetics} }