Genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD
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
Background
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.
Methods
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.
Results
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.
Conclusion
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.
