Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding

Sarah K. Westbury, Matthias Canault, Daniel Greene, Emilse Bermejo, Katharine Hanlon, Michele P. Lambert, Carolyn M. Millar, Paquita Nurden, Samya G. Obaji, Shoshana Revel-Vilk, Chris Van Geet, Kate Downes, Sofia Papadia, Salih Tuna, Christopher Watt, Kathleen Freson, Michael A. Laffan, Willem H. Ouwehand, Marie Christine Alessi, Ernest TurroAndrew D. Mumford

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenicRASGRP2variants,wecompared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out aIIbb3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 59-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessivePFDassociatedwith amoderate or severe bleeding phenotype and complex defects in platelet aggregation.

Original languageEnglish
Pages (from-to)1026-1030
Number of pages5
JournalBlood
Volume130
Issue number8
DOIs
StatePublished - 24 Aug 2017
Externally publishedYes

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