TY - JOUR
T1 - International initiative for a curated SDHB variant database improving the diagnosis of hereditary paraganglioma and pheochromocytoma
AU - Ben Aim, Laurene
AU - Maher, Eamonn R.
AU - Cascon, Alberto
AU - Barlier, Anne
AU - Giraud, Sophie
AU - Ercolino, Tonino
AU - Pigny, Pascal
AU - Clifton-Bligh, Roderick J.
AU - Mirebeau-Prunier, Delphine
AU - Mohamed, Amira
AU - Favier, Judith
AU - Gimenez-Roqueplo, Anne Paule
AU - Schiavi, Francesca
AU - Toledo, Rodrigo A.
AU - Dahia, Patricia L.
AU - Robledo, Mercedes
AU - Bayley, Jean Pierre
AU - Burnichon, Nelly
N1 - Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
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U2 - 10.1136/jmedgenet-2020-107652
DO - 10.1136/jmedgenet-2020-107652
M3 - Article
C2 - 34452955
AN - SCOPUS:85134855119
SN - 0022-2593
VL - 59
SP - 785
EP - 792
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 8
ER -