Hereditary platelet function disorder from <i>RASGRP2</i> gene mutations encoding CalDAG-GEFI identified by whole-exome sequencing in a Korean woman with severe bleeding

Yun, Jae Won; Lee, Ki O.; Jung, Chul Won; Oh, Soo Young; Kim, Sun Hee; Choi, Chul Won; Kim, Hee Jin

doi:10.3324/haematol.2019.218487

Cited by 9 publications

(8 citation statements)

References 15 publications

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“…IPFD associated with RASGRP2 mutation is a new category of disease called BDPLT18, a very rare disorder with severe primary hemostatic symptoms. There are approximately 20 RASGRP2 mutations reported worldwide [ 17 , 18 ]. Pathogenic variants in RASGRP2 lead to non-syndromic platelet dysfunction inherited in an autosomal recessive manner [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG)

Yang

Shim

Kim

et al. 2021

Genes

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The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March 2017 to December 2020, aimed to identify the causative genetic variants of IPFDs in Korean patients using next-generation sequencing (NGS). Targeted exome sequencing, followed by whole-genome sequencing, was performed for diagnosing IPFDs. Of the 11 unrelated patients with suspected IPFDs enrolled in this study, 10 patients and 2 of their family members were diagnosed with Glanzmann thrombasthenia (GT). The variant c.1913+5G>T of ITGB3 was the most common, followed by c.2333A>C (p.Gln778Pro) of ITGB2B. Known variants of GT, including c.917A>C (p.His306Pro) of ITGB3 and c.2975del (p.Glu992Glyfs*), c.257T>C (p.Leu86Pro), and c.1750C>T (p.Arg584*) of ITGA2B, were identified. Four novel variants of GT, c.1451G>T (p.Gly484Val) and c.1595G>T (p.Cys532Phe) of ITGB3 and c.1184G>T (p.Gly395Val) and c.2390del (p.Gly797Valfs*29) of ITGA2B, were revealed. The remaining patient was diagnosed with platelet type bleeding disorder 18 and harbored two novel RASGRP2 variants, c.1479dup (p.Arg494Alafs*54) and c.813+1G>A. We demonstrated the successful application of NGS for the accurate and differential diagnosis of heterogeneous IPFDs.

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Section: Discussionmentioning

confidence: 99%

Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG)

Yang

Shim

Kim

et al. 2021

Genes

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

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

Al‐Hebshi

2020

Cureus

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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. RAS guanyl-releasing protein-2 (RASGRP2) was recently identified as a gene affected in patients with 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 guanosine triphosphate(GTP)ase 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.

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“…Pregnancy should be managed in close collaboration with the specialized center in hemostasis, with a written management plan for the affected mother, and also a plan for investigation and management of the neonate, if necessary. We and others recently reported two cases of successful management of bleeding diathesis during the course of pregnancy and peripartum period in two women woman suffering BDPLT18 [90,100]. The neonate is not at risk of inheriting the full platelet function disorder unless the father is a carrier, although it should be noted that minor to no symptoms are seen in individuals who are heterozygous carriers of RasGRP2 variants.…”

Section: Patient Managementmentioning

confidence: 90%

“…She was then transfused with two units of leukocyte-reduced red blood cells and started an iron replacement therapy. She did not show any other medical issue during the one-month follow-up [90]. As in Glanzmann thrombasthenia, women need to be closely observed and tranexamic acid continued for at least several weeks and to have ready access to the obstetric service in connection with the hemostasis expert center.…”

Section: Patient Managementmentioning

confidence: 98%

“…The mutation corresponds to a homozygous G to T transition in exon 13 (c.1507G>T) that leads to the replacement of a glutamic acid residue to a stop codon (p.E503*) ( Table 2, "referenced as newly identified variant"). [92] in dark green, Yun et al [90] in purple, Lunghi et al [93] in dark blue, Manukjan et al [94] in pink and the newly identified variant id indicated in red. Variants in brackets are prediction of intronic modifications affecting splice regions.…”

Section: Rasgrp2 Gene Variationsmentioning

confidence: 99%

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RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology

Canault

Alessi

2020

IJMS

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RasGRP2 is calcium and diacylglycerol-regulated guanine nucleotide exchange factor I that activates Rap1, which is an essential signaling-knot in “inside-out” αIIbβ3 integrin activation in platelets. Inherited platelet function disorder caused by variants of RASGRP2 represents a new congenital bleeding disorder referred to as platelet-type bleeding disorder-18 (BDPLT18). We review here the structure of RasGRP2 and its functions in the pathophysiology of platelets and of the other cellular types that express it. We will also examine the different pathogenic variants reported so far as well as strategies for the diagnosis and management of patients with BDPLT18.

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Hereditary platelet function disorder from RASGRP2 gene mutations encoding CalDAG-GEFI identified by whole-exome sequencing in a Korean woman with severe bleeding

Cited by 9 publications

References 15 publications

Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG)

Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG)

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

RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology

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