Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma

Jean Pierre Bayley*, Birke Bausch, Johannes Adriaan Rijken, Leonie Theresia Van Hulsteijn, Jeroen C. Jansen, David Ascher, Douglas Eduardo Valente Pires, Frederik J. Hes, Erik F. Hensen, Eleonora P.M. Corssmit, Peter Devilee, Hartmut P.H. Neumann

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background Pathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype. Methods Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes. Results Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001). Conclusions SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.

Original languageEnglish
Pages (from-to)96-103
Number of pages8
JournalJournal of Medical Genetics
Volume57
Issue number2
DOIs
Publication statusPublished - 1 Feb 2020

Cite this

Bayley, J. P., Bausch, B., Rijken, J. A., Van Hulsteijn, L. T., Jansen, J. C., Ascher, D., ... Neumann, H. P. H. (2020). Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma. Journal of Medical Genetics, 57(2), 96-103. https://doi.org/10.1136/jmedgenet-2019-106214