Tumor Risks and Genotype-Phenotype-Proteotype Analysis in 358 Patients With Germline Mutations in SDHB and SDHD

Christopher J. Ricketts, Julia R. Forman, Eleanor Rattenberry, Nicola Bradshaw, Fiona Lalloo, Louise Izatt, Trevor R. Cole, Ruth Armstrong, V. K. Ajith Kumar, Patrick J. Morrison, A. Brew Atkinson, Fiona Douglas, Steve G. Ball, Jackie Cook, Umasuthan Srirangalingam, Pip Killick, Gail Kirby, Simon Aylwin, Emma R. Woodward, D. Gareth R. EvansShirley V. Hodgson, Vicky Murday, Shern L. Chew, John M. Connell, Tom L. Blunde, Fiona MacDonald, Eamonn R. Maher

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    311 Citations (Scopus)


    Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n = 295) and SDHD (n = 63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma, risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma. Hum Mutat 31:41-51, 2010. (C) 2009 Wiley-Liss, Inc.

    Original languageEnglish
    Pages (from-to)41-51
    Number of pages11
    JournalHuman Mutation
    Issue number1
    Publication statusPublished - Jan 2010


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