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Blood. 2017 Aug 24;130(8):1026-1030. doi: 10.1182/blood-2017-03-776773. Epub 2017 Jun 21.

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

Author information

1
School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
2
National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.
3
Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France.
4
Centre de Référence sur les Pathologies Plaquettaires, Centre Hospitalier Universitaire Timone, Marseille, France.
5
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
6
Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom.
7
Hematological Research Institute, National Academy of Medicine, Buenos Aires, Argentina.
8
Department of Haematology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
9
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.
10
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
11
Centre for Haematology, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom.
12
Imperial College Healthcare National Health Service Trust, London, United Kingdom.
13
Institut Hospitalo-Universitaire LIRYC, Hôpital Xavier Arnozan, Pessac, France.
14
Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
15
Pediatric Hematology/Oncology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
16
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
17
National Health Service Blood and Transplant, Cambridge, United Kingdom.
18
Wellcome Trust Sanger Institute, Cambridge, United Kingdom; and.
19
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.

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 pathogenic RASGRP2 variants, we compared 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 αIIbβ3 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 5'-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, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.

PMID:
28637664
PMCID:
PMC5785798
DOI:
10.1182/blood-2017-03-776773
[Indexed for MEDLINE]
Free PMC Article

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