Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug;59(8):785-792.
doi: 10.1136/jmedgenet-2020-107652. Epub 2021 Aug 27.

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

Laurene Ben Aim  1 , Eamonn R Maher  2 , Alberto Cascon  3 , Anne Barlier  4 , Sophie Giraud  5 , Tonino Ercolino  6 , Pascal Pigny  7 , Roderick J Clifton-Bligh  8 , Delphine Mirebeau-Prunier  9 , Amira Mohamed  4 , Judith Favier  10 , Anne-Paule Gimenez-Roqueplo  1   10 , Francesca Schiavi  11 , Rodrigo A Toledo  12 , Patricia L Dahia  13 , Mercedes Robledo  3 , Jean Pierre Bayley  14 , Nelly Burnichon  15   10
Affiliations

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

Laurene Ben Aim et al. J Med Genet. 2022 Aug.

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.

Keywords: adrenal gland diseases; databases; genetic; genetic testing; genetic variation; human genetics.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Distribution of SDHB variants according to the type of alteration RGT: rearrangement. UTR, untranslated region.
Figure 2
Figure 2
Diagram of the coding SDHB variants along the amino acid sequence L(I)YR motifs are shown in blue. The cysteine residues ligating the [Fe2-S2], the [Fe4-S4] and the [Fe3-S4] are shown in orange, red and purple, respectively. Diagram is displayed as lollipop symbols designed using the Mutation Mapper tool of the cBioPortal website. The Y axis represents the number of occurrences of variant in one residue.
Figure 3
Figure 3
Strategy for variant classification. ACMG, American College of Medical Genetics and Genomics; BV, benign variant; LBV, likely benign variant; LPV, likely pathogenic variant; PV, pathogenic variant; VUS, variant of unknown significance.
Figure 4
Figure 4
Distribution of SDHB variant types according to the 5-tier classification. VUS, variant of unknown significance; UTR, untranslated region.
See this image and copyright information in PMC

References

    1. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49–54. 10.1086/321282 - DOI - PMC - PubMed
    1. NGS in PPGL (NGSnPPGL) Study Group, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley J-P, Welander J, Tops CM, Firth H, Dwight T, Ercolino T, Mannelli M, Opocher G, Clifton-Bligh R, Gimm O, Maher ER, Robledo M, Gimenez-Roqueplo A-P, Dahia PLM. Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol 2017;13:233–47. 10.1038/nrendo.2016.185 - DOI - PubMed
    1. Lenders JWM, Duh Q-Y, Eisenhofer G, Gimenez-Roqueplo A-P, Grebe SKG, Murad MH, Naruse M, Pacak K, Young WF, Endocrine Society . Pheochromocytoma and paraganglioma: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014;99:1915–42. 10.1210/jc.2014-1498 - DOI - PubMed
    1. Lenders JWM, Kerstens MN, Amar L, Prejbisz A, Robledo M, Taieb D, Pacak K, Crona J, Zelinka T, Mannelli M, Deutschbein T, Timmers HJLM, Castinetti F, Dralle H, Widimský J, Gimenez-Roqueplo A-P, Eisenhofer G. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working group on endocrine hypertension of the European Society of hypertension. J Hypertens 2020;38:1443–56. 10.1097/HJH.0000000000002438 - DOI - PMC - PubMed
    1. Ben Aim L, Pigny P, Castro-Vega LJ, Buffet A, Amar L, Bertherat J, Drui D, Guilhem I, Baudin E, Lussey-Lepoutre C, Corsini C, Chabrier G, Briet C, Faivre L, Cardot-Bauters C, Favier J, Gimenez-Roqueplo A-P, Burnichon N. Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. J Med Genet 2019;56:513–20. 10.1136/jmedgenet-2018-105714 - DOI - PubMed

Publication types

MeSH terms

Substances