Analysis of Gene Variants: An Invaluable Aid to Diagnosis
Several platelet function disorders are now known to be caused by rare gene variants, and these can be identified and validated (see Table 1).5,6,7,8 In other disorders, clinical and laboratory evaluations usually do not provide sufficient evidence to target the candidate gene(s). Enrichment of target DNA together with next generation sequencing (NGS) enables molecular analysis of a large number of candidate genes within a limited and relevant gene set as part of early diagnosis.9,10
Proper identification of causative gene variants relies on a comprehensive knowledge of current genomic sequence information. Carefully curated databases, such as Reactome (www.reactome.org),9 are a source of relevant information for physicians and scientists about cellular pathways and the relationships between rare sequence variants and clinical phenotypes.
Additional valuable information is available through the Locus Reference Genome (LRG) (www.lrg-sequence.org), a curated system that establishes consensus single gene DNA sequences and an annotation layer of sequence variants that can be updated.
In the area of hemostasis/thrombosis, the ThromboGenomics project (https://haemgen.haem.cam.ac.uk/thrombogenomics), sponsored by the International Society on Thrombosis and Haemostasis (ISTH), provides a stable and sustainable frame of reference for identification of relevant gene variants that can improve the diagnosis of inherited bleeding disorders. Curation for four platelet disorders (Glanzmann thrombasthenia, Bernard-Soulier syndrome, Wiskott-Aldrich syndrome and familial platelet disorder with predisposition to acute myelogenous leukemia) has been completed, and locus reference genomes have been created for seven genes: ITGA2B, ITGB3, GP1BA, GP1BB, GP9, WAS and RUNX1.
Other current efforts include a newly developed Platelet Working Group at the Clinical Genomics Resource (https://www.clinicalgenome.org) sponsored by the National Institute of Health (NIH) and the American Society of Hematology (ASH), which actively collaborates with the ThromboGenomics group. These projects will hopefully guarantee adequate curation of genetic variants associated with megakaryocytes and platelet phenotypes.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
