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They're not your daddy's inherited platelet disorders anymore

Although individual inherited platelet disorders (IPDs) are rare, in aggregate – especially when including those IPDs resulting in milder bleeding symptoms or thrombocytopenia – they may be as prevalent as von Willebrand disease, the most common inherited bleeding disorder. A few ‘classic’ IPDs have been characterized for many years, with their molecular basis having been delineated. Two of the earliest, Bernard–Soulier syndrome and Glanzmann thrombasthenia, have been molecularly characterized for over 20 years. Others, such as platelet-type von Willebrand disease, familial Mediterranean thrombocytopenia, Wiskott–Aldrich syndrome, and the MYH9related disorders, were more recently characterized, and are among the IPDs that can be diagnosed by a combination of clinic history, physical examination, and standard laboratory studies, including an assortment of platelet morphologic and functional studies. Confirmatory, targeted-gene analyses are often performed. Although many IPD investigators have focused on refining recommended roadmaps based on these technologies, in the end, > 50% of patients who are likely to be affected remain partially characterized and without a molecular diagnosis. In others, it remains unclear even whether they actually have an IPD. Increasingly, IPD investigators are recognizing that modern proteomic and genomic technologies could be the focus in the analysis of patients with IPDs, replacing many non-definitive, expensive and time-consuming studies. Some have suggested that whole exome sequencing or even whole genome sequencing may become a first line to identify the molecular basis of rare diseases [1]. We believe that the family IPD study described by Stevenson et al. [2] in this issue of JTH presents the strengths of such a genomics-centric approach: after clear family evidence of an IPD had been obtained, a single-nucleotide polymorphism array localized the molecular defect to chromosome 9, and massive parallel sequencing analysis then identified the molecular defect in this family, a single nucleotide insertion in GFI1B. Their report is an outstanding example of standard initial clinical evaluation combined with the power and efficiency of genomic analysis. In the end, they define a new basis for autosomal dominant macrothrombocytopenia, perhaps the most prevalent clinical phenotype in the IPDs. This knowledge not only allowed for better definitive diagnosis and care of affected family members, but also provided new insights into this phenotype and the role of GFI1B in human megakaryopoiesis and erythropoiesis. The identified defect – an insertional mutation within a conserved zinc finger domain in a transcription factor that is important in hematopoiesis, GFI1B [3] – results in a frameshift mutation. The authors then use various cell culture and reporter assays to confirm that the suspected molecular defect not only localizes only to affect individuals within the kindred, but also results in a phenotype within experimental constructs. Without the power of genomic analysis, characterization would have stopped at the point of saying that this family did not have any of the previously known disorders resulting in macrothrombocytopenia. GFI1B is a transcription factor previously shown in murine studies to be involved in erythroid and megakaryocyte development [3] and in human normal and malignant hematopoiesis [4], but had not been described as causing macrothrombocytopenic IPD with qualitative platelet defects. In this article, it becomes clear that mutations of GFI1B result in changes in platelet morphology, function and a-granule number, and in red cell morphological changes, perhaps because of changes in cytoskeletal elements. Remarkably, these changes are similar to the platelet phenotype Correspondence: Michele P. Lambert, Children’s Hospital of Philadelphia, Abramson Research Center, Rm 316G, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA. Tel.: +1 215 590 4667; fax: +1 215 590 4834. E-mail: lambertm@email.chop.edu