Article Text

Original research
Germline mutations in the new E1’ cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma
  1. Alexandre Buffet1,
  2. Bruna Calsina2,
  3. Shahida Flores3,
  4. Sophie Giraud4,5,
  5. Marion Lenglet6,7,
  6. Pauline Romanet8,
  7. Elisa Deflorenne1,
  8. Javier Aller9,
  9. Isabelle Bourdeau10,
  10. Brigitte Bressac-de Paillerets5,11,
  11. María Calatayud12,
  12. Caroline Dehais13,
  13. Erwan De Mones Del Pujol14,
  14. Atanaska Elenkova15,
  15. Philippe Herman16,
  16. Peter Kamenický17,
  17. Sophie Lejeune5,18,
  18. Jean Louis Sadoul19,
  19. Anne Barlier5,8,
  20. Stephane Richard5,6,20,
  21. Judith Favier1,
  22. Nelly Burnichon1,21,
  23. Betty Gardie6,7,
  24. Patricia L Dahia3,
  25. Mercedes Robledo2,
  26. Anne-Paule Gimenez-Roqueplo1,5,21
  1. 1 Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France
  2. 2 Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  3. 3 Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
  4. 4 Genetics Department, Hospices Civils de LYON (HCL), University Hospital, East Biology and Pathology Center, B-A3, 59 Bld Pinel, 69677, Bron, France
  5. 5 Réseau National pour Cancers Rares PREDIR labellisé par l’Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
  6. 6 École Pratique des Hautes Études, PSL Research University, Paris, France
  7. 7 L'Institut du Thorax, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France
  8. 8 Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France
  9. 9 Endocrinology and Nutrition Service. Hospital Universitario Puerta de Hierro, 28222, Majadahonda, Spain
  10. 10 Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Quebec, Canada
  11. 11 Gustave Roussy, Université Paris-Saclay, Département de Biopathologie and INSERM U1186, Villejuif, F-94805, France
  12. 12 Department of Endocrinology and Nutrition, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
  13. 13 Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France
  14. 14 Service ORL, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France
  15. 15 Department of Endocrinology, USHATE “Acad. Ivan Penchev”, Medical University Sofia, Sofia, Bulgaria
  16. 16 Assistance Publique, Hôpitaux de Paris, Service ORL-CCF, hôpital Lariboisière, université Paris VII, Paris, France
  17. 17 Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin Bicetre, France
  18. 18 Department of Clinical Genetics, Centre Hospitalier Régional et Universitaire de Lille, Lille, France
  19. 19 Service d'Endocrinologie, Hôpital de L'Archet, CHU de Nice, Nice, France
  20. 20 Génétique Oncologique EPHE, INSERM U1186, Gustave Roussy Cancer Campus, Villejuif, France
  21. 21 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
  1. Correspondence to Dr Alexandre Buffet, Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France; alexandre.buffet{at}


Backgrounds The incidence of germline mutations in the newly discovered cryptic exon (E1’) of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.

Methods We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum (‘Single VHL tumour’ cohort), 70 patients with multiple tumours of the VHL spectrum (‘Multiple VHL tumours’ cohort), 76 patients with a VHL disease as described in the literature (‘VHL-like’ cohort) and 946 patients with a PPGL were screened for E1’ genetic variants.

Results Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum.

Conclusions VHL E1’ cryptic exon mutations contribute to 1.32% (1/76) of ‘VHL-like’ cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.

  • von Hippel-Lindau
  • paraganglioma
  • cryptic exon

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

View Full Text

Statistics from

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • BC, SF, SG and ML contributed equally.

  • Contributors APGR conceived and supervised the study. ABu, APGR, MR, PLD and BG designed the study and analysed the results. JF and NB participated to the data analysis. ABu., BC, SF, SG, ML and ED designed and performed the experiments. PR, JA, IB, BBdP, MC, CD EdM, AE, PH, PK, SL, JLS, ABa, SR, BG, PLD, MR and APGR collected subjects and clinical parameters. ABu and APGR wrote the manuscript. ABu prepared the figures and the tables. All the authors discussed the results and commented the manuscript.

  • Funding ABu received a financial support from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan and from la Fondation pour la Recherche Médicale (FDT20170436955). SF is currently supported by an NIH-NIGMS individual predoctoral fellowship grant (F31-GM131634-01) and, previously, by an NIH NRSA Institutional Predoctoral Training Grant T32CA148724 and NRSA F31-GM131634-01. PLD receives funding support from NIH-GM114102, Alex’s Lemonade Stand Cancer Foundation (Innovation Award) and the NCATS- UL1 TR002645. The Genomic Sequencing Facility at the GCCRI is supported by the P30-CA54174 (CTRC at UTHSCSA) and NIH Shared Instrument grant 1S10OD021805-01 (S10 grant). BC is supported by Rafael del Pino Foundation. MR receives funding support from Instituto de Salud Carlos III (ISCIII), through the 'Acción Estratégica en Salud' (AES) (projects PI17/01796), cofounded by the European Regional Development Fund (ERDF), and the Paradifference Foundation.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement All available data are in the article.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.