The genes encoding the coagulation factor proteins were among the first human genes to be characterized over 25 years ago. Since then, significant progress has been made in the translational application of this information for the 2 commonest severe inherited bleeding disorders, hemophilia A and B. For these X-linked disorders, genetic characterization of the disease-causing mutations is now incorporated into the standard of care and genetic information is used for risk stratification of treatment complications. With electronic databases detailing >2100 unique mutations for hemophilia A and >1100 mutations for hemophilia B, these diseases are among the most extensively characterized inherited diseases in humans. Experience with the genetics of the rare bleeding disorders is, as expected, less well advanced. However, here again, electronic mutation databases have been developed and provide excellent guidance for the application of genetic analysis as a confirmatory approach to diagnosis. Most recently, progress has also been made in identifying the mutant loci in a variety of inherited platelet disorders, and these findings are beginning to be applied to the genetic diagnosis of these conditions. Investigation of patients with bleeding phenotypes without a diagnosis, using genome-wide strategies, may identify novel genes not previously recognized as playing a role in hemostasis. (Blood. 2013; 122(20):3423-3431)
Future genomic strategies for the characterization of inherited bleeding disorders
As genomic technologies continue to advance, the potential for incorporating these strategies into diagnostic algorithms will inevitably increase. However, before this can happen, a number of critical additions to our current diagnostic infrastructure must be developed.
Carefully curated databases, such as Reactome (www.reactome. org), provide key information that will enable physicians and scientists to access relevant information on cellular pathways and to visualize the relationships between rare sequence variants and clinical phenotypes. The GEN2PHEN database (www.gen2phen.org), created through a collaboration between the National Center for Bioinformatics and European Bioinformatics Institute, and other efforts have resulted in the establishment of the Locus Reference Genome (www.lrg-sequence. org), a system that provides a genomic DNA sequence representing a single gene, whose core content never changes, with an updateable annotation layer that includes sequence variants.
