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

Abstract

Adrenal gland diseases; Databases; Genetic variation

Enfermedades de las glándulas suprarrenales; Bases de datos; Variación genética

Malalties de les glàndules suprarenals; Bases de dades; Variació genètica

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.

This work was supported in part by a salary grant to NB from Cancer Research for PErsonalized Medicine (CARPEM). ERM acknowledges funding from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre) and Cancer Research UK Cambridge Cancer Centre. The University of Cambridge has received salary support in respect of ERM from the NHS in the East of England through the Clinical Academic Reserve. PLD receives support from the National Institutes of Health (NIH)-National Institute of General Medical Science (NIGMS) GM114102, NIH-National Center for Advancing Translational Science (NCATS) Clinical Translational Science Award (CTSA) UL1 TR001120 and UL1 TR002645, the Mays Cancer Center NIH-National Cancer Institute (NCI) P30 CA54174, Alex’s Lemonade Childhood Foundation, with support from Northwest Mutual and Flashes of Hope, and University of Texas Health SystemSTARS Award. RAT holds a Miguel Servet-I research contract by Institute of Health Carlos III (ISCIII) of the Ministry of Economy (CP17/00199) and Competitiveness; is supported by an Olga Torres Foundation Emerging researcher grant and by the Swiss Bridge Award for cancer immunotherapy research; and received research grants from BeiGene, Novartis and AstraZeneca. Cancer Genetics, Kolling Institute, Sydney acknowledges support from the Hillcrest Foundation (Perpetual Trustees). JPB in Leiden, The Netherlands acknowledges support from the Paradifference Foundation. MR is supported by the Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofounded by FEDER (grant number PI17/01796).