Inherited platelet disorders: towards DNA-based diagnosis

Claire Lentaigne, Kathleen Freson, Michael A. Laffan, Ernest Turro and Willem H. Ouwehand


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 (GWAS)1. The genome also contains a large number of rare variants, of which a tiny fraction underlie the inherited diseases of man. Research over the past three decades have led to the discovery of 51 genes harbouring 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 (HTS). Finally, we describe how integration of large genomic, epigenomic and phenotypic datasets, including whole genome sequencing (WGS) data, GWAS, epigenomic profiling, protein-protein interaction networks and standardised clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

  • Submitted March 29, 2016.
  • Accepted April 13, 2016.