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Essentials    Mutations in the  RASGRP2  gene represent a new inherited platelet function disorder.  Report a five generation family with a novel frameshift mutation in  RASGRP2  (p.F497Sfs*22).  Partial platelet activation defect and serious bleeding complications in homozygous patients.  Patients respond to recombinant Factor VIIa infusion but not platelet transfusions.Background  Genetic variants in the   RASGRP 2  gene encoding calcium and diacylglycerol‐regulated guanine nucleotide exchange factor I (Cal DAG ‐ GEFI ) represent a new inherited bleeding disorder linked to major defects of platelet aggregation and activation of α II bβ3 integrin. They are of major interest as Cal DAG ‐ GEFI  is receiving attention as a potential target for antiplatelet therapy for prevention and treatment of cardiovascular disorders including arterial thrombosis and atherosclerosis.    Objectives  To better understand the phenotypical and clinical profiles of patients with Cal DAG ‐ GEFI  deficiency.    Patients  We report a five‐generation family with a novel truncating Cal DAG ‐ GEFI  mutation detailing clinical management and phenotypic variability.    Results  Patients  IV .6 &  IV .4 manifested with episodes of serious mucocutanous bleeding or bleeding after surgery not responding to platelet transfusion but responding well to recombinant Factor  VII a infusions. Their blood counts and coagulation parameters were normal but platelet aggregation to  ADP  and collagen was defective. Further work‐up confirmed normal levels of α II b and β3 in their platelets but decreased α II bβ3 function.  DNA  analysis by whole exome sequencing within the  BRIDGE ‐ BPD  consortium (Cambridge,  UK ), allowed us to highlight a homozygous c.1490delT predicted to give rise to a p.F497Sfs*22 truncating mutation near to the C‐terminal domain of Cal DAG ‐ GEFI . Sanger sequencing confirmed that both patients were homozygous for the c.1490delT and 3 out of 4 close family members were heterozygous.    Conclusions  A long‐term prospective study is warranted for full clinical exploration of Cal DAG ‐ GEFI  to understand the bleeding phenotyes and their management.

Phenotype analysis and clinical management in a large family with a novel truncating mutation in RASGRP2 , the CalDAG‐GEFI encoding gene