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)

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.

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

“…A pediatric group in Korea used targeted WES and then WGS to genotype 11 patients with IPDs chosen on the basis of their clinical phenotype (with a normal platelet count) but for whom only limited platelet function testing was available. 53 Ten were shown to have homozygous or compound heterozygous mutations of ITGA2B or ITGB3. Their work helped confirm c.1913 þ 5G > Tof ITGB3 as a founder mutation in Korea.…”

Classic Light Transmission Platelet Aggregometry: Do We Still Need it?

“…The defect may be caused by quantitative or qualitative abnormalities of the platelet integrin receptor, αIIbβ3, the primary player in platelet function. While Glanzmann's thrombasthenia shows a straightforward pattern of aggregation using LTA, describing the pathology at the genetic molecular level reveals a wide variety of polymorphisms, [137][138][139] leading to the observed pathology. 42 To exemplify, 45 unrelated patients who were unequivocally diagnosed with Glanzmann's thrombasthenia based on their phenotype were subjected for the genetic analysis in αIIb and β3 genes.…”