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Original research
SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma
  1. Jean Pierre Bayley1,
  2. Birke Bausch2,
  3. Jeroen C Jansen3,
  4. Erik F Hensen4,5,
  5. Karin van der Tuin6,
  6. Eleonora PM Corssmit7,
  7. Peter Devilee8,
  8. Hartmut PH Neumann9
  1. 1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Medicine II, University of Freiburg Faculty of Medicine, Freiburg, Germany
  3. 3Department of Otorhinolaryngology, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  4. 4Department of Otorhinolaryngology - Head & Neck Surgery, VU Medisch Centrum, Amsterdam, The Netherlands
  5. 5Department of Otolaryngology - Head and Neck Surgery, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  7. 7Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
  8. 8Departments of Human Genetics and Pathology, Leiden University Medical Center, Leiden, The Netherlands
  9. 9Department of Nephrology, Universitätsklinikum Freiburg, Freiburg, Germany
  1. Correspondence to Dr Jean Pierre Bayley, Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; J.P.L.Bayley{at}lumc.nl

Abstract

Background Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy.

Methods We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis.

Results Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant.

Conclusion SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.

  • genotype
  • phenotype
  • adrenal gland diseases
  • endocrine gland neoplasms

Data availability statement

Data are available in a public, open access repository. All data analysed in this study can be found as supplemental files to the article Bayley et al. J Med Genet. 2020 Feb;57(2):96-103.or Andrews et al. J Med Genet 2018;55:384-94.

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Data availability statement

Data are available in a public, open access repository. All data analysed in this study can be found as supplemental files to the article Bayley et al. J Med Genet. 2020 Feb;57(2):96-103.or Andrews et al. J Med Genet 2018;55:384-94.

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Footnotes

  • Contributors JPB planned the study, analysed the data and wrote the manuscript. HPHN, EPMC and PD helped plan the study and write the manuscript. BB, KvdT, JCJ, EFH, EPMC and HPHN collected data and edited the manuscript.

    JPB is the guarantor of this study and accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding This work was supported by the Dutch Cancer Society (Grant 2011-5025 to JPB/PD).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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