Abstract
SummaryBackgroundInherited platelet function disorders (PFDs) are heterogeneous, and identification of the underlying genetic defects is difficult when based solely on phenotypic and clinical features of the patient.ObjectiveTo analyze 329 genes regulating platelet function, number, and size in order to identify candidate gene defects in patients with PFDs.Patients/methodsTargeted analysis of candidate PFD genes was undertaken after next‐generation sequencing of exomic DNA from 18 unrelated index cases with PFDs who were recruited into the UK Genotyping and Phenotyping of Platelets (GAPP) study and diagnosed with platelet abnormalities affecting either Gi signaling (n = 12) or secretion (n = 6). The potential pathogenicity of candidate gene defects was assessed using computational predictive algorithms.ResultsAnalysis of the 329 candidate PFD genes identified 63 candidate defects, affecting 40 genes, among index cases with Gi signaling abnormalities, while 53 defects, within 49 genes, were identified among patients with secretion abnormalities. Homozygous gene defects were more commonly associated with secretion abnormalities. Functional annotation analysis identified distinct gene clusters in the two patient subgroups. Thirteen genes with significant annotation enrichment for ‘intracellular signaling’ harbored 16 of the candidate gene defects identified in nine index cases with Gi signaling abnormalities. Four gene clusters, representing 14 genes, with significantly associated gene ontology annotations were identified among the cases with secretion abnormalities, the most significant association being with ‘establishment of protein localization.’ConclusionOur findings demonstrate the genetic complexity of PFDs and highlight plausible candidate genes for targeted analysis in patients with platelet secretion and Gi signaling abnormalities.
Highlights
Inherited platelet function disorders (PFDs), associated with normal or reduced platelet counts, are characterized by lifelong episodes of excessive mucocutaneous bleeding and account for a significant proportion of bleeding diatheses [1]
We describe the results of a targeted analysis of 329 platelet genes, which are known or predicted to have a role in regulating platelet function, size, and number, in 18 unrelated index patients diagnosed with PFDs and recruited to the UK-Genotyping and Phenotyping of Platelets (GAPP) study and shown to have defects in either Gi receptor signaling or dense granule secretion
A subgroup of 18 index cases (F1.1 to F18.1; 13 females and five males), who ranged in age from 6 to 82 years, and were recruited into the UK GAPP study [3,18] on the basis of abnormal bleeding symptoms and a suspected inherited platelet disorder, were investigated
Summary
Inherited platelet function disorders (PFDs), associated with normal or reduced platelet counts, are characterized by lifelong episodes of excessive mucocutaneous bleeding and account for a significant proportion of bleeding diatheses [1]. First described in 1962, light transmission aggregometry (LTA) remains the gold standard method for diagnosing PFDs, while assessment of platelet-dense granule ATP release provides an additional valuable tool for diagnosing platelet secretion disorders [2]. Most PFDs can be assigned to one of three major diagnostic groups having defects in the thromboxane A2 pathway, Gi receptor signaling, and dense granule secretion, with the latter two groups accounting for almost two-thirds of those participants who had a defect in platelet aggregation or ATP secretion [3]. In most cases, identification of the causative gene based solely on the clinical and laboratory phenotype is rarely achieved in PFDs due to the heterogeneity and complexity of these disorders
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