
Phenotype analysis and clinical management in a large family with a novel truncating mutation in RASGRP2 , the CalDAG‐GEFI encoding gene
Author(s) -
Desai Amrita,
Bergmeier Wolfgang,
Canault Mathias,
Alessi MarieChristine,
Paul David S.,
Nurden Paquita,
Pillois Xavier,
Jy Wenche,
Ahn Yeon S.,
Nurden Alan T.
Publication year - 2017
Publication title -
research and practice in thrombosis and haemostasis
Language(s) - English
Resource type - Journals
ISSN - 2475-0379
DOI - 10.1002/rth2.12019
Subject(s) - medicine , platelet disorder , blood platelet disorders , platelet , mutation , platelet activation , gene , genetics , biology , platelet aggregation
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.