TY - JOUR
T1 - Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding
AU - Westbury, Sarah K.
AU - Canault, Matthias
AU - Greene, Daniel
AU - Bermejo, Emilse
AU - Hanlon, Katharine
AU - Lambert, Michele P.
AU - Millar, Carolyn M.
AU - Nurden, Paquita
AU - Obaji, Samya G.
AU - Revel-Vilk, Shoshana
AU - Van Geet, Chris
AU - Downes, Kate
AU - Papadia, Sofia
AU - Tuna, Salih
AU - Watt, Christopher
AU - Freson, Kathleen
AU - Laffan, Michael A.
AU - Ouwehand, Willem H.
AU - Alessi, Marie Christine
AU - Turro, Ernest
AU - Mumford, Andrew D.
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/8/24
Y1 - 2017/8/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85028454412&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-03-776773
DO - 10.1182/blood-2017-03-776773
M3 - Article
C2 - 28637664
AN - SCOPUS:85028454412
SN - 0006-4971
VL - 130
SP - 1026
EP - 1030
JO - Blood
JF - Blood
IS - 8
ER -