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

Author:

Ben Aim Laurene,Maher Eamonn RORCID,Cascon Alberto,Barlier Anne,Giraud Sophie,Ercolino Tonino,Pigny PascalORCID,Clifton-Bligh Roderick J,Mirebeau-Prunier Delphine,Mohamed Amira,Favier Judith,Gimenez-Roqueplo Anne-Paule,Schiavi Francesca,Toledo Rodrigo A,Dahia Patricia L,Robledo Mercedes,Bayley Jean PierreORCID,Burnichon NellyORCID

Abstract

BackgroundSDHB 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.MethodsA 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.ResultsThis 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).ConclusionThis 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.

Funder

nih nci

National Center for Advancing Translational Sciences

National Institute of General Medical Sciences

NIH Clinical translational science award

Instituto de Salud Carlos III

Cancer Research UK Cambridge Cancer Centre

Publisher

BMJ

Subject

Genetics (clinical),Genetics

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