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

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Title: Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding
Author(s): Westbury, SK
Canault, M
Greene, D
Bermejo, E
Hanlon, K
Lambert, MP
Millar, CM
Nurden, P
Obaji, SG
Revel-Vilk, S
Van Geet, C
Downes, K
Papadia, S
Tuna, S
Watt, C
Freson, K
Laffan, MA
Ouwehand, WH
Alessi, M-C
Turro, E
Mumford, AD
Item Type: Journal Article
Abstract: Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls. Eleven cases harboured 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included five high-impact variants predicted to prevent CalDAG-GEFI expression and six missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signalling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical and dental bleeding from childhood, requiring at least one blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to ADP 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 non-syndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.
Publication Date: 24-Aug-2017
Date of Acceptance: 11-Jun-2017
URI: http://hdl.handle.net/10044/1/53259
DOI: https://dx.doi.org/10.1182/blood-2017-03-776773
ISSN: 1528-0020
Publisher: American Society of Hematology
Start Page: 1026
End Page: 1030
Journal / Book Title: Blood
Volume: 130
Issue: 8
Copyright Statement: © 2017 by The American Society of Hematology
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/J011711/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Hematology
GENETIC-VARIANTS
WORLDWIDE SURVEY
CALDAG-GEFI
DISORDERS
DIAGNOSIS
THROMBOCYTOPENIA
ACTIVATION
MUTATIONS
DEFECTS
ISTH
Alleles
Base Sequence
Blood Platelets
Female
Guanine Nucleotide Exchange Factors
Hemorrhage
Humans
Male
Mutation
Pedigree
NIHR BioResource–Rare Diseases Consortium
Blood Platelets
Humans
Hemorrhage
Guanine Nucleotide Exchange Factors
Pedigree
Base Sequence
Mutation
Alleles
Female
Male
Science & Technology
Life Sciences & Biomedicine
Hematology
GENETIC-VARIANTS
WORLDWIDE SURVEY
CALDAG-GEFI
DISORDERS
DIAGNOSIS
THROMBOCYTOPENIA
ACTIVATION
MUTATIONS
DEFECTS
ISTH
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Immunology
Publication Status: Published
Embargo Date: 2018-08-24
Appears in Collections:Department of Medicine
Epidemiology, Public Health and Primary Care



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