Key result
Rare missense variants in TPM4 (p.R182C and p.A183V) were identified in 3 patients with excessive bleeding and were associated with reduced platelet secretion, aggregation, and spreading defects.
Why the study?
Genetic diagnosis of inherited platelet disorders is challenging due to numerous candidate genes, frequent variants of unknown significance, and the need for functional studies to prove pathogenicity.
Case Report (n=3)
Rare missense variants in TPM4 are associated with platelet dysfunction and excessive bleeding, highlighting TPM4 as a diagnostic grade tier 1 gene for inherited platelet disorders.
This is the authors' abstract. We don't add key points for this paper.
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.
Functional studies may aid VUS reclassification in inherited platelet disorders; leaves open standardized assay validation for clinical use.
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Stapley et al. (2021) conducted a case report in Suspected platelet disorder and excessive bleeding (n=3). Rare missense variants in TPM4 (p.R182C and p.A183V) was evaluated on Platelet function defects (reduced platelet secretion, aggregation, and spreading defects). Rare missense variants in TPM4 (p.R182C and p.A183V) were identified in 3 patients with excessive bleeding and were associated with reduced platelet secretion, aggregation, and spreading defects.
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