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).

Eu Jeen Yang ,Hyery Kim,Young Tak Lim ,Jeong Ok Hah ,Heung Sik Kim ,Ji Soo Ha ,Jae Min Lee ,Kyung‐Nam Koh ,Young Bae Choi ,Jung Woo Han ,Hye Lim Jung ,Na Hee Lee ,Ho Joon Im ,Ye Jee Shim ,Jae Hee Lee ,Jin Kyung Suh ,Eun Sil Park ,Young-Ho Lee,Chang‐Seok Ki

doi:10.3390/genes12050693

Abstract

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.

Highlights

Inherited platelet function disorders (IPFDs) are a heterogeneous disease group associated with congenital defects in platelet function, including adhesion, activation, signal transduction, granule secretion, aggregation, and procoagulant activity [1,2]
Using next-generation sequencing (NGS), 10 cases were genetically confirmed as Glanzmann thrombasthenia (GT), whereas one was a case of platelet type bleeding disorder 18 (BDPLT18)
light transmission aggregometry (LTA) and flow cytometry (FC) are among the first-line tests for the differential diagnosis of inherited platelet function disorders (IPFDs)

Summary

Introduction

Inherited platelet function disorders (IPFDs) are a heterogeneous disease group associated with congenital defects in platelet function, including adhesion, activation, signal transduction, granule secretion, aggregation, and procoagulant activity [1,2]. Glanzmann thrombasthenia (GT) (OMIM #273800) is the most representative IPFD with a life-long bleeding phenotype [3]. It is an autosomal recessive disorder characterized by a failure of platelet aggregation due to quantitative or qualitative defects in the glycoprotein (GP)-IIb/GP-IIIa complex caused by mutations in ITGA2B or ITGB3 [3]. It is difficult to accurately diagnose and identify each IPFD case in Korea, and the prevalence of IPFDs in Korean patients and the distribution of their genetic abnormalities remain unknown. Only anecdotal cases of GT have been genetically confirmed and reported in Korea [2,6]. This study aimed to perform genetic confirmation and differential diagnosis of Korean IPFDs using next-generation sequencing (NGS)

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