International initiative for a curatedvariant database improving the diagnosis of hereditary paraganglioma and pheochromocytoma.

in Journal of medical genetics by Laurene Ben Aim, Eamonn R Maher, Alberto Cascon, Anne Barlier, Sophie Giraud, Tonino Ercolino, Pascal Pigny, Roderick J Clifton-Bligh, Delphine Mirebeau-Prunier, Amira Mohamed, Judith Favier, Anne-Paule Gimenez-Roqueplo, Francesca Schiavi, Rodrigo A Toledo, Patricia L Dahia, Mercedes Robledo, Jean Pierre Bayley, Nelly Burnichon

TLDR

  • The study looked at the gene SDHB and its role in paraganglioma/pheochromocytoma (PPGL). The study collected 223 distinct variants from 737 patients worldwide and used multiple criteria to classify each variant according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations. The study then manually reviewed each variant by a panel of experts in the field, resulting in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). The study's consensus classification for genetic variants in SDHB can be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis, which will help to clarify the diagnosis of hereditary PPGL and improve the clinical care of patients and relatives with PPGL. The study also highlights the importance of expert curation in the classification of genetic variants.

Abstract

is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenicvariants 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 classifyvariants and to provide an accurate, expert-curated and freely availablevariant database. A total of 223 distinctvariants 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. 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). This international initiative by a panel of experts allowed us to establish a consensus classification for 223variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification ofgenetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.

Overview

  • The study focuses on the gene SDHB and its role in paraganglioma/pheochromocytoma (PPGL).
  • The study aims to establish a consensus classification for genetic variants in SDHB that can be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. The study collected 223 distinct variants from 737 patients worldwide and used multiple criteria to classify each variant according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations. The study then manually reviewed each variant by a panel of experts in the field, resulting in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS).
  • The primary objective of the study is to establish a consensus classification for genetic variants in SDHB that can be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The study identified 223 distinct variants from 737 patients worldwide and used multiple criteria to classify each variant according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations. The study then manually reviewed each variant by a panel of experts in the field, resulting in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS).
  • The study found that expert curation reduced by half the number of variants initially classified as VUS. The study also established a consensus classification for 223 variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study's consensus classification for genetic variants in SDHB can be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis, which will help to clarify the diagnosis of hereditary PPGL and improve the clinical care of patients and relatives with PPGL. The study also highlights the importance of expert curation in the classification of genetic variants. Future research directions could include expanding the study to include other genes predisposing to PPGL and exploring the use of machine learning algorithms in the classification of genetic variants.
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