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

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

Diagnostics and Intervention in Developmental Dyscalculia: Current Issues and Novel Perspectives

Developmental dyscalculia is one of the most prevalent learning disorders observed in children. However, it has received much less research interest than, for instance, developmental dyslexia. Thus our knowledge about aetiology, aetiopathology and symptomatology of dyscalculia remains patchy; and empirically validated approaches on remediation and intervention are still scarce. In the current chapter we first discuss the theoretical underpinnings of developmental dyscalculia, paying particular attention to its still debated aetiology: Some authors suggest the heterogeneous symptoms of developmental dyscalculia to be caused by a single underlying deficit of the number sense, while others propose different deficits in basic numerical competencies as its determinants (as observed in adult acalculia). Second, the implications of this differentiation on dyscalculia diagnostics are discussed. In particular, we focus on the importance of cut off criteria, sample selection, and their influence on the epidemiology of developmental dyscalculia. In a third section, the issue of comorbidity and its estimation will be evaluated. And finally, existing intervention approaches are reviewed in light of their theoretical underpinnings and practical applications. We conclude that we are on a promising way to better understand, diagnose and treat brain-based dyscalculia with innovative novel methodology.publishe