Evaluating the clinical validity of genes related to hemostasis and thrombosis using the Clinical Genome Resource gene curation framework

Justyne E Ross; Shruthi Mohan; Jing Zhang; Mia J Sullivan; Loredana Bury; Kristy Lee; Isabella Futchi; Annabelle Frantz; Dara McDougal; Juliana Perez Botero; Marco Cattaneo; Nichola Cooper; Kate Downes; Paolo Gresele; Catriona Keenan; Alfred I Lee; Karyn Megy; Pierre-Emmanuel Morange; Neil V Morgan; Harald Schulze; Karen Zimowski; Kathleen Freson; Michele P Lambert

doi:10.1016/j.jtha.2023.11.011

Evaluating the clinical validity of genes related to hemostasis and thrombosis using the Clinical Genome Resource gene curation framework

J Thromb Haemost. 2024 Mar;22(3):645-665. doi: 10.1016/j.jtha.2023.11.011. Epub 2023 Nov 26.

Authors

Justyne E Ross¹, Shruthi Mohan¹, Jing Zhang², Mia J Sullivan³, Loredana Bury⁴, Kristy Lee¹, Isabella Futchi¹, Annabelle Frantz¹, Dara McDougal¹, Juliana Perez Botero⁵, Marco Cattaneo⁶, Nichola Cooper⁷, Kate Downes⁸, Paolo Gresele⁴, Catriona Keenan⁹, Alfred I Lee¹⁰, Karyn Megy⁸, Pierre-Emmanuel Morange¹¹, Neil V Morgan¹², Harald Schulze¹³, Karen Zimowski¹⁴, Kathleen Freson¹⁵, Michele P Lambert¹⁶

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
² KingMed Diagnostics, Guangzhou, Guangdong, China.
³ Versiti Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
⁴ Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.
⁵ Versiti Blood Center of Wisconsin, Milwaukee, Wisconsin, USA; Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁶ Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.
⁷ Centre for Haematology, Imperial College London, London, UK.
⁸ Department of Haematology, University of Cambridge, Cambridge, UK.
⁹ Haemostasis Molecular Diagnostic Laboratory, National Coagulation Centre, St James's Hospital, Dublin, Ireland.
¹⁰ Section of Hematology, Yale School of Medicine, New Haven, Connecticut, USA.
¹¹ INSERM, INRAE, C2VN, Aix Marseille University, Marseille, France; Hematology Laboratory, La Timone Hospital, APHM, Marseille, France.
¹² Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
¹³ Institute of Experimental Biomedicine, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany.
¹⁴ Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹⁵ Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. Electronic address: kathleen.freson@kuleuven.be.
¹⁶ Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: LAMBERTM@chop.edu.

PMID: 38016518
PMCID: PMC10922649 (available on 2025-03-01)
DOI: 10.1016/j.jtha.2023.11.011

Abstract

Background: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are very rare globally. Over the past 5 decades, the genetic basis of some of these disorders has been identified, and recently, high-throughput sequencing has become the primary means of identifying disease-causing genetic variants.

Objectives: Knowledge of the clinical validity of a gene-disease relationship is essential to provide an accurate diagnosis based on results of diagnostic gene panel tests and inform the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Hemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose of the process was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes associated with BTPDs.

Methods: The Clinical Genome Resource (ClinGen) Hemostasis/Thrombosis Gene Curation Expert Panel assessed the strength of evidence for TIER1 genes using the semiquantitative ClinGen gene-disease clinical validity framework. ClinGen Lumping and Splitting guidelines were used to determine the appropriate disease entity or entities for each gene, and 101 gene-disease relationships were identified for curation.

Results: The final outcome included 68 Definitive (67%), 26 Moderate (26%), and 7 Limited (7%) classifications. The summary of each curation is available on the ClinGen website.

Conclusion: Expert-reviewed assignment of gene-disease relationships by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel facilitates accurate molecular diagnoses of BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.

Keywords: data curation; genetic disorders; genetic variation; hemostasis; reliability and validity; thrombosis.

MeSH terms

Blood Platelet Disorders* / genetics
Genetic Testing / methods
Genetic Variation
Hemostasis / genetics
Humans
Thrombosis* / diagnosis
Thrombosis* / genetics

Abstract

MeSH terms

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