Inherited platelet disorders: toward DNA-based diagnosis.
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.
Centre for Haematology, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom;
Claire
0000-0003-0406-4776
C
Lentaigne
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
Kathleen
0000-0002-4381-2442
K
Freson
Centre for Haematology, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom;
Michael A
0000-0002-8268-3268
MA
Laffan
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom; and.
Ernest
0000-0002-1820-6563
E
Turro
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom; and Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
Willem H
0000-0002-7744-1790
WH
Ouwehand
D001791:Blood Platelet Disorders / Q000175:diagnosis* / Q000235:genetics*; D001792:Blood Platelets / Q000502:physiology; D004247:DNA / Q000032:analysis / Q000097:blood; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D025202:Molecular Diagnostic Techniques / Q000379:methods / Q000639:trends*; D035583:Rare Diseases / Q000175:diagnosis / Q000235:genetics; D034061:Thrombopoiesis / Q000235:genetics
D004247:DNA