International initiative for a curated SDHB variant database improving the diagnosis of hereditary paraganglioma and pheochromocytoma

Journal of Medical Genetics, vol. 59, pp. 785–792

Abstract

Background SDHB is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenic SDHB variants in patients with PPGL is essential to the management of patients and relatives due to the increased risk of recurrences, metastases and the emergence of non-PPGL tumours. In this context, the ‘NGS and PPGL (NGSnPPGL) Study Group’ initiated an international effort to collect, annotate and classify SDHB variants and to provide an accurate, expert-curated and freely available SDHB variant database. Methods A total of 223 distinct SDHB variants from 737 patients were collected worldwide. Using multiple criteria, each variant was first classified according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations and was then manually reviewed by a panel of experts in the field. Results This multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system ( https://databases.lovd.nl/shared/genes/SDHB ). Conclusion This international initiative by a panel of experts allowed us to establish a consensus classification for 223 SDHB variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification of SDHB genetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.

Authors 18

1. Laurène Ben Aim

   Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou

   Affiliation as printed

   Genetics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France

2. Eamonn Richard Maher

   University of Cambridge · NIHR Cambridge Biomedical Research Centre

   Affiliation as printed

   Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK

3. Alberto Cascón

   Spanish National Cancer Research Centre

   Affiliation as printed

   Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain

4. Anne Barlier

   Hôpital de la Conception

   Affiliation as printed

   Laboratory of Molecular Biology, La Conception Hospital, Marseille, France

5. Sophie Giraud

   Hospices Civils de Lyon

   Affiliation as printed

   Department of Genetics, Hospices Civils de Lyon, Bron, France

6. Tonino Ercolino

   Azienda Ospedaliero-Universitaria Careggi

   Affiliation as printed

   Endocrinology Unit, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy

7. Pascal Pigny

   Centre Hospitalier Universitaire de Lille

   Affiliation as printed

   Institut de Biochimie & Biologie Moléculaire, Lille University Hospital Center, Lille, France

8. Roderick John Clifton-Bligh

   The University of Sydney · Royal North Shore Hospital

   Affiliation as printed

   Department of Endocrinology, Royal North Shore Hospital, Kolling Institute, University of Sydney, Sydney, New South Wales, Australia

9. Delphine Mirebeau‐Prunier

   Centre Hospitalier Universitaire d'Angers

   Affiliation as printed

   Département de Biochimie et Génétique, CHU Angers, Angers, France

10. Amira Husseiny Mohamed

    Hôpital de la Conception

    Affiliation as printed

    Laboratory of Molecular Biology, La Conception Hospital, Marseille, France

11. Judith Favier

    Inserm · Université Paris Cité · La Ligue Contre le Cancer · Paris Cardiovascular Research Center

    Affiliation as printed

    Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, Paris, France

12. Anne‐Paule Gimenez‐Roqueplo

    Inserm · Université Paris Cité · La Ligue Contre le Cancer · Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou · Paris Cardiovascular Research Center

    Affiliation as printed

    Genetics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France

    Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, Paris, France

13. Francesca Schiavi

    Istituto Oncologico Veneto

    Affiliation as printed

    Familial Cancer Clinic and Oncoendocrinology, IOV IRCCS, Padova, Italy

14. Rodrigo Almeida Toledo

    Centro de Investigación Biomédica en Red de Cáncer · Vall d'Hebron Institute of Oncology

    Affiliation as printed

    CIBERONC, Gastrointestinal and Endocrine Tumors, VHIO, Barcelona, Spain

15. Patricia L. M. Dahia

    The University of Texas at San Antonio Health Science Center · Mays Cancer Center at UT Health San Antonio

    Affiliation as printed

    Department of Medicine, Division of Hematology and Medical Oncology, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

16. Mercedes Robledo

    Spanish National Cancer Research Centre

    Affiliation as printed

    Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain

17. Jean‐Pierre Bayley Aachen Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Human Genetics, LUMC, Leiden, The Netherlands

18. Nelly Burnichon corresponding

    Inserm · Université Paris Cité · La Ligue Contre le Cancer · Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou · Paris Cardiovascular Research Center

    Affiliation as printed

    Genetics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France

    Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, Paris, France

    Team 13, UMR970 PARCC-HEGP, 75015 Paris, France