Genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD


Session type:

Christopher Ricketts1, Julia Forman2, Eleanor Rattenbury3, Nicola Bradshaw4, Fiona MacDonald3, Eamonn Maher1

1CR-UK Renal Molecular Oncology Group, Medical & Molecular Genetics, University of Birmingham, UK, 2University of Cambridge, UK, 3West Midlands Region Genetics Service, Birmingham Womens Hospital, UK, 4Duncan Guthrie Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK


Proffered paper presentation

Germline mutations in the B and D subunits of succinate dehydrogenase are a frequent cause of genetic susceptibility to adrenal and extra-adrenal phaeochromocytomas and head and neck paragangliomas (HNPGL) and may also predispose to other tumour types such as notably renal and thyroid cancera and gastrointestinal stromal tumours (GIST). However, accurate estimation of tumour risks have been limited by marked intra- and interfamilial variations in phenotype.

We analysed age-related tumour risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. In addition, we investigated the relationship between clinical phenotype and (a) mutation type and (b) the structure of the mutant protein.

Overall penetrance and risk of HNPGL was higher in SDHD mutation carriers whilst lifetime risk of developing a malignant phaeochromocytoma was higher in SDHB mutation carriers. Risk of developing renal tumours in SDHB and SDHD mutation carriers was 14% and 8% at age 70 years. 55 different mutations were identified including a novel exon 1 deletion in three unrelated kindreds. The structural consequences of SDHB and SDHD mutations were predicted and genotype-proteotype-phenotype correlations analysed. SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with increased penetrance and risk of phaeochromocytoma. The common p.Pro81Leu accounted for most of the patients with SDHD mutations that did not impair protein stability and was associated with a high risk of HNPGL but low risk of phaeochromocytoma.

Analysis of the largest cohort of SDHB/D mutation carriers has provided more accurate estimates of penetrance and tumour risk. In silico protein structure prediction analysis can facilitates assessment of potential missense mutations. The differential effect of the p.Pro81Leu on HNPGL and phaeochromocytoma risks highlights differences in mechanisms of tumourigenesis between SDH-mutation associated HNPGL and phaeochromocytoma.