Genetic classification and confirmation of inherited platelet disorders: current status in Korea

Abstract

Inherited platelet disorders (IPDs), which manifest as primary hemostasis defects, often underlie abnormal bleeding and a family history of thrombocytopenia, bone marrow failure, hematologic malignancies, undefined mucocutaneous bleeding disorder, or congenital bony defects. Wide heterogeneity in IPD types with regard to the presence or absence of thrombocytopenia, platelet dysfunction, bone marrow failure, and dysmegakaryopoiesis is observed in patients. The individual processes involved in platelet production and hemostasis are genetically controlled; to date, mutations of more than 50 genes involved in various platelet biogenesis steps have been implicated in IPDs. Representative IPDs resulting from defects in specific pathways, such as thrombopoietin/MPL signaling; transcriptional regulation; granule formation, trafficking, and secretion; proplatelet formation; cytoskeleton regulation; and transmembrane glycoprotein signaling are reviewed, and the underlying gene mutations are discussed based on the National Center for Biotechnology Information database and Online Mendelian Inheritance in Man accession number. Further, the status and prevalence of genetically confirmed IPDs in Korea are explored based on searches of the PubMed and KoreaMed databases. IPDs are congenital bleeding disorders that can be dangerous due to unexpected bleeding and require genetic counseling for family members and descendants. Therefore, the pediatrician should be suspicious and aware of IPDs and perform the appropriate tests if the patient has unexpected bleeding. However, all IPDs are extremely rare; thus, the domestic incidences of IPDs are unclear and their diagnosis is difficult. Diagnostic confirmation or differential diagnoses of IPDs are challenging, time-consuming, and expensive, and patients are frequently misdiagnosed. Comprehensive molecular characterization and classification of these disorders should enable accurate and precise diagnosis and facilitate improved patient management.

Diagnostic workup of inherited platelet disorders

“… Platelet function pathway and biology related to each stage of megakaryopoiesis, and genes found to be associated with inherited platelet disorder (IPDs) (modified from [ 1 , 7 , 10 ]). …”

“…The prevalence of IPDs is considered very low, approximately 1 in 10 4-6 persons worldwide [ 4 , 5 ]. In Korea, the exact prevalence is unknown, although sporadic cases have been reported [ 6 , 7 ].…”

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 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 ].…”

“…Thus, 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. Thus far, 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).…”

When to suspect inherited platelet disorders and how to diagnose them

“…2,3) BSS is a rare autosomal recessive bleeding disorder characterized by defects of the GPIbIXV complex, a platelet receptor for VWF and moderate thrombocytopenia and giant platelets on a peripheral blood smear. 2,3) Shim 7) described that genetic abnormalities of IPDs identified in recent studies by genomewide association study and next generation sequencing and genetically confirmed Korean IPD patients. The recent Korean Pediatric HematologyOncology Group (KPHOG) study using targeted exome sequencing in multiple Korean centers was also presented.…”