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. 2022 Feb;20(2):478-485.
doi: 10.1111/jth.15584. Epub 2021 Nov 21.

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

Rachel J Stapley  1 , Natalie S Poulter  1   2 , Abdullah O Khan  1 , Christopher W Smith  1 , Patricia Bignell  3 , Carl Fratter  3 , Will Lester  4 , Gillian Lowe  4 , Neil V Morgan  1 ; UK GAPP Study Group
Collaborators, Affiliations
Free article

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

Rachel J Stapley et al. J Thromb Haemost. 2022 Feb.
Free article

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] J Thromb Haemost. 2022 Jun;20(6):1511. doi: 10.1111/jth.15719. J Thromb Haemost. 2022. PMID: 35596517 No abstract available.

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: TPM4; bleeding; cytoskeleton; next generation sequencing; platelet disorder; platelet dysfunction.

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References

REFERENCES

    1. Nurden AT, Nurden P. Congenital platelet disorders and understanding of platelet function. Br J Haematol. 2014;165:165-178.
    1. Nurden P, Stritt S, Favier R, Nurden AT. Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy. Haematologica. 2021;106:337-350.
    1. Downes K, Megy K, Duarte D, et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019;134:2082-2091.
    1. Almazni I, Stapley RJ, Khan AO, Morgan NV. A comprehensive bioinformatic analysis of 126 patients with an inherited platelet disorder to identify both sequence and copy number genetic variants. Hum Mutat. 2020;41:1848-1865.
    1. Lentaigne C, Freson K, Laffan MA, Turro E, Ouwehand WH. Inherited platelet disorders: toward DNA-based diagnosis. Blood. 2016;127:2814-2823.

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