Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding.

Stapley, Rachel J ORCID: 0000-0002-0027-9158, Poulter, Natalie S ORCID: 0000-0002-3187-2130, Khan, Abdullah O ORCID: 0000-0003-0825-3179, Smith, Christopher W, Bignell, Patricia, Fratter, Carl, Lester, Will, Lowe, Gillian, Morgan, Neil V ORCID: 0000-0001-6433-5692 and UK GAPP Study Group, (2022) Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding. Journal of thrombosis and haemostasis : JTH, 20 (2). pp. 478-485.

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Official URL: http://dx.doi.org/10.1111/jth.15584

Abstract

<h4>Background</h4>A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity.<h4>Objective</h4>To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found.<h4>Methods</h4>Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry.<h4>Results</h4>We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining.<h4>Conclusions</h4>Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count.

Item Type:	Article
Uncontrolled Keywords:	UK GAPP Study Group, Humans, Blood Platelet Disorders, Thrombocytopenia, Hemorrhage, Tropomyosin, Mutation, Missense
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	14 Oct 2022 08:28
Last Modified:	18 Jan 2023 20:36
DOI:	10.1111/jth.15584
Open Access URL:	https://doi.org/10.1111/jth.15584
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3165453