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Phenotype analysis and clinical management in a large family with a novel truncating mutation in RASGRP2, the

Amrita Desai1, Wolfgang Bergmeier2, Mathias Canault3

  • 1Division of Hematology/Oncology University of Miami Miami FL USA.

Research and Practice in Thrombosis and Haemostasis
|July 27, 2018
PubMed

Insights

Novel genetic variants in RASGRP2 cause inherited bleeding disorders due to platelet defects. This study identifies a new mutation affecting CalDAG-GEFI, impacting platelet aggregation and offering insights for cardiovascular therapies.

Area of Science:

  • Hematology
  • Genetics
  • Cardiovascular Medicine

Background:

  • Genetic variants in RASGRP2, encoding CalDAG-GEFI, are linked to inherited bleeding disorders.
  • CalDAG-GEFI is crucial for platelet aggregation and αIIbβ3 integrin activation.
  • CalDAG-GEFI is a potential therapeutic target for cardiovascular disorders like arterial thrombosis.

Purpose of the Study:

  • To characterize the phenotypical and clinical profiles of patients with CalDAG-GEFI deficiency.
  • To investigate a novel truncating CalDAG-GEFI mutation within a five-generation family.

Main Methods:

  • Clinical management and phenotypic variability were detailed for affected individuals.
  • Whole exome sequencing identified a homozygous c.1490delT mutation in RASGRP2.
  • Sanger sequencing confirmed the mutation in affected family members.

Main Results:

  • Patients presented with severe mucocutaneous bleeding and post-surgical bleeding, unresponsive to platelet transfusions.
  • Platelet aggregation to ADP and collagen was defective, with reduced αIIbβ3 integrin function.
  • A novel homozygous truncating mutation (p.F497Sfs*22) in CalDAG-GEFI was identified.

Conclusions:

  • The identified mutation causes a significant bleeding disorder linked to CalDAG-GEFI deficiency.
  • Recombinant Factor VIIa showed efficacy in managing bleeding episodes.
  • Further long-term studies are needed to fully understand CalDAG-GEFI's role in bleeding phenotypes and management.
Abstract

Keywords:
CalDAG‐GEFIRASGRP2 genebleeding syndromeclinical managementinherited platelet disorder

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