Inherited platelet disorders: toward DNA-based diagnosis

Abstract

Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).1 The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein–protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

“…The work‐up of patients with mild bleeding disorders is hampered by the fact that the number of possible causes is extensive (>51 different inherited platelet abnormalities have been genetically described) but the incidence of each defect is very low (<1/100 000) (Nurden & Nurden, 2013; Lentaigne et al , 2016). Some patients may have several defects working in concert to produce a mild bleeding disorder (Stockley et al , 2015).…”

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

“…Rare mutations of the genes encoding thrombopoietin ( THPO ) and its receptor ( MPL ) result in congenital thrombocytopenia 17. Several transcription factors have also been implicated in the differentiation process (see Table 1).…”

Speaker Abstracts

“…The enormous potential and increasingly competitive price of HTS are reasons that favor its use as the first option for the molecular diagnosis of diseases in a clinical setting, 10 including IPDs and other hemorrhagic disorders. 4,[11][12][13] Indeed, the irruption of HTS has revolutionized the field of IPDs, leading to identification of many new disorders. 4,14,15,14,15 Our project "Functional and molecular characterization of patients with IPDs" has involved so far 150 patients suspected to have an IPD.…”