Inherited Platelet Function Disorder From Novel Mutations in RAS Guanyl-Releasing Protein-2 Confirmed by Sanger Sequencing

Abstract

Background: Inherited platelet disorders (IPDs), are genetically heterogeneous rare disorders due to quantitative and/or qualitative abnormalities of the platelet. IPDs are often predisposed to significant medical complications. RASGRP2 (RAS guanyl-releasing protein-2) was recently identified as a gene affected in patients with a platelet function defects and a bleeding complication. RASGRP2 codes for the protein CalDAG-GEFI RAS (guanyl-releasing protein-2), a guanine nucleotide exchange factor for small GTPase Rap1. We used Sanger sequencing to identify a novel function-disrupting homozygous mutation in RASGRP2 responsible for bleeding diathesis and platelet dysfunction in a patient. Aims: Reporting a rare causes of platelet dysfunction Methods: Case Report Results: A novel mutation in RASGRP2 causuing Inherited platelet disorders dThere is a consistent laboratory phenotype of reduced aggregation response to ADP (adenosine 5'-diphossphate) and epinephrine, but not defect indense granule secretion, distinguishing this disorder from d-storage disease [11] Pathogenic RASGRP2 variants are causative for autosomal recessive platelet-type bleeding disorder type 18 (BDPLT18) gene (605577) on chromosome 11q13. It is a rare hematological disease due to a CalDAG-GEFI deficiency (OMIMR615888). With a prevalence of < 1/1000000 globally, the age of onset and the clinical course are observed in the infancy period. According to our literature review, Canault et al. (2014) reported three siblings, born of consanguine parents, with a bleeding disorder due to defective platelet function [1]. The parents developed mucocutaneous bleeding around 18 months of age. Features included epistaxis, hematomas, bleeding after tooth extraction, and menorrhagia. Bleeding times were increase, and the patient's platelets indicated a reduced aggregation in response to ADP or epinephrine. Canault et al. identified a homozygous mutation in the RASGRP2 gene (G248W; 605577.0001). The mutation was found by exome sequencing and segregated with the disorder in the family [12]. With the current case, we report a novel pathogenic RASGRP2 mutation c956C > T.(Pro319Leu) which causes an amino acid change from Pro to Leu at position 319. During the first presentation of our patient, Glanzmann thrombasthenia was initially suspected as the mother has a history of oozing after a cut wound but the sequencing analysis of ITGA2B, ITGB3 as well as VWF gene was normal [13]. Further work was done using Clinical Exome Sequencing, which revealed a potential positive result for a variant of uncertain significance, which has been confirmed by the Sanger sequencing as a homozygous variant of uncertain significance with the parents being carriers of the same variant. Consequently, the diagnosis of an autosomal recessive platelet-type bleeding 18 with novel mutation was confirmed [14]. This type of variant was classified as variant of uncertain significance (class 3) according to the recommendations Summary/Conclusion: I report a case of platelet-type bleeding disorder type 18, based on a novel mutation in RASGRP2 affecting the expression and/or function of CalDAG-GEFI. Such a defect will impair the aggregation response to certain agonists, most prominently ADP and collagen, this will delay the aggregation causing clinical bleeding episodes with varying severity. Our findings, combined with the previous study, strengthen the molecular heterogeneity of RASGRP2 as a cause of inherited platelet disorders, which will facilitate obtaining information about the phenotype, prognosis as well as support a medical management decision.