Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen 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 Lee; Karyn Megy; Pierre Morange; Neil 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 ClinGen 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 Lee, Karyn Megy, Pierre Morange, Neil Morgan, Harald SchulzeKaren Zimowski, Kathleen Freson^*, Michele P.Lambert^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are globally very rare. Over the past five 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 both providing an accurate diagnosis based on results of diagnostic gene panel tests and informing the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose 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 ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel (HT GCEP) assessed the strength of evidence for TIER1 genes using the semi-quantitative 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 seven Limited (7%) classifications. The summary of each curation is available on the ClinGen website.

Conclusions: Expert-reviewed assignment of gene-disease relationships by the HT GCEP facilitates accurate molecular diagnoses for BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.

Original language	English
Journal	Thrombosis and Haemostasis
Early online date	26 Nov 2023
DOIs	https://doi.org/10.1016/j.jtha.2023.11.011
Publication status	E-pub ahead of print - 26 Nov 2023

Access to Document

10.1016/j.jtha.2023.11.011

Embargoed Document

RossJ2023Evaluating
Accepted author manuscript, 997 KB
Licence: None: All rights reserved
Embargo ends: 26/11/24

Cite this

Ross, J. E., Mohan, S., Zhang, J., Sullivan, M. J., Bury, L., Lee, K., Futchi, I., Frantz, A., McDougal, D., Perez Botero, J., Cattaneo, M., Cooper, N., Downes, K., Gresele, P., Keenan, C., Lee, A., Megy, K., Morange, P., Morgan, N., ... P.Lambert, M. (2023). Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen gene curation framework. Thrombosis and Haemostasis. Advance online publication. https://doi.org/10.1016/j.jtha.2023.11.011

@article{97a82e183bbe450eb988b23902295f8a,

title = "Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen gene curation framework",

abstract = "Background: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are globally very rare. Over the past five 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 both providing an accurate diagnosis based on results of diagnostic gene panel tests and informing the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose 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 ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel (HT GCEP) assessed the strength of evidence for TIER1 genes using the semi-quantitative 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 seven Limited (7%) classifications. The summary of each curation is available on the ClinGen website. Conclusions: Expert-reviewed assignment of gene-disease relationships by the HT GCEP facilitates accurate molecular diagnoses for BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease. ",

author = "Ross, {Justyne E.} and Shruthi Mohan and Jing Zhang and Sullivan, {Mia J.} and Loredana Bury and Kristy Lee and Isabella Futchi and Annabelle Frantz and Dara McDougal and {Perez Botero}, Juliana and Marco Cattaneo and Nichola Cooper and Kate Downes and Paolo Gresele and Catriona Keenan and Alfred Lee and Karyn Megy and Pierre Morange and Neil Morgan and Harald Schulze and Karen Zimowski and Kathleen Freson and Michele P.Lambert",

year = "2023",

month = nov,

day = "26",

doi = "10.1016/j.jtha.2023.11.011",

language = "English",

journal = "Thrombosis and Haemostasis",

issn = "0340-6245",

publisher = "Schattauer",

}

Ross, JE, Mohan, S, Zhang, J, Sullivan, MJ, Bury, L, Lee, K, Futchi, I, Frantz, A, McDougal, D, Perez Botero, J, Cattaneo, M, Cooper, N, Downes, K, Gresele, P, Keenan, C, Lee, A, Megy, K, Morange, P, Morgan, N, Schulze, H, Zimowski, K, Freson, K & P.Lambert, M 2023, 'Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen gene curation framework', Thrombosis and Haemostasis. https://doi.org/10.1016/j.jtha.2023.11.011

TY - JOUR

T1 - Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen gene curation framework

AU - Ross, Justyne E.

AU - Mohan, Shruthi

AU - Zhang, Jing

AU - Sullivan, Mia J.

AU - Bury, Loredana

AU - Lee, Kristy

AU - Futchi, Isabella

AU - Frantz, Annabelle

AU - McDougal, Dara

AU - Perez Botero, Juliana

AU - Cattaneo, Marco

AU - Cooper, Nichola

AU - Downes, Kate

AU - Gresele, Paolo

AU - Keenan, Catriona

AU - Lee, Alfred

AU - Megy, Karyn

AU - Morange, Pierre

AU - Morgan, Neil

AU - Schulze, Harald

AU - Zimowski, Karen

AU - Freson, Kathleen

AU - P.Lambert, Michele

PY - 2023/11/26

Y1 - 2023/11/26

N2 - Background: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are globally very rare. Over the past five 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 both providing an accurate diagnosis based on results of diagnostic gene panel tests and informing the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose 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 ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel (HT GCEP) assessed the strength of evidence for TIER1 genes using the semi-quantitative 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 seven Limited (7%) classifications. The summary of each curation is available on the ClinGen website. Conclusions: Expert-reviewed assignment of gene-disease relationships by the HT GCEP facilitates accurate molecular diagnoses for BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.

AB - Background: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are globally very rare. Over the past five 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 both providing an accurate diagnosis based on results of diagnostic gene panel tests and informing the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose 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 ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel (HT GCEP) assessed the strength of evidence for TIER1 genes using the semi-quantitative 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 seven Limited (7%) classifications. The summary of each curation is available on the ClinGen website. Conclusions: Expert-reviewed assignment of gene-disease relationships by the HT GCEP facilitates accurate molecular diagnoses for BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.

U2 - 10.1016/j.jtha.2023.11.011

DO - 10.1016/j.jtha.2023.11.011

M3 - Article

SN - 0340-6245

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

ER -

Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen gene curation framework

Abstract

Access to Document

Embargoed Document

Fingerprint

Cite this