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Original article
Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma–paraganglioma
  1. Jean Pierre Bayley1,
  2. Birke Bausch2,
  3. Johannes Adriaan Rijken3,
  4. Leonie Theresia van Hulsteijn4,
  5. Jeroen C Jansen5,
  6. David Ascher6,
  7. Douglas Eduardo Valente Pires7,
  8. Frederik J Hes8,
  9. Erik F Hensen5,
  10. Eleonora P M Corssmit9,
  11. Peter Devilee10,
  12. Hartmut P H Neumann11
  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 – Head & Neck Surgery, Free University Medical Center, Amsterdam, The Netherlands
  4. 4Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Department of Otorhinolaryngology, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Biochemistry and Molecular Biology, The University of Melbourne Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia
  7. 7Instituto René Rachou, Fundacao Oswaldo Cruz, Belo Horizonte, Brazil
  8. 8Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  9. 9Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
  10. 10Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  11. 11Section for Preventive Medicine, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
  1. Correspondence to Dr Jean Pierre Bayley, Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands; J.P.L.Bayley{at}lumc.nl

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.

  • paraganglioma
  • pheochromocytoma
  • Succinate dehydrogenase
  • SDHB
  • SDHC
  • SDHD
  • genotype-phenotype
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Footnotes

  • Contributors JPB planned the study, analysed the data and wrote the manuscript. PD planned the study and provided supervision. BB, JAR, LTvH, JCJ, FJH, EFH, EPMC and HPHN collected data and edited the manuscript. DA and DEVP analysed data. JPB is responsible for the overall content and guarantees the content of the manuscript.

  • Funding This work was supported by the Dutch Cancer Society (Grant 2011-5025 to JPB/PD) and by the Jack Brockhoff Foundation (JBF 4186, 2016 to DA); National Health and Medical Research Council of Australia (APP1072476 to DA); Australian Cancer Research Foundation (to DA), Australia Awards – Endeavour Fellowship (to DEVP); Instituto René Rachou (IRR/FIOCRUZ Minas), Brazil and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (to DEVP); and Department of Biochemistry and Molecular Biology, University of Melbourne (to DA).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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