Abstract
Inherited platelet disorders (IPD) form a rare and heterogeneous disease entity that is present in about 8% of patients with non-acquired bleeding diathesis. Identification of the defective cellular pathway is an important criterion for stratifying the patient's individual risk profile and for choosing personalized therapeutic options. While costs of high-throughput sequencing technologies have rapidly declined over the last decade, molecular genetic diagnosis of bleeding and platelet disorders is getting more and more suitable within the diagnostic algorithms. In this study, we developed, verified, and evaluated a targeted, panel-based next-generation sequencing approach comprising 59 genes associated with IPD for a cohort of 38 patients with a history of recurrent bleeding episodes and functionally suspected, but so far genetically undefined IPD. DNA samples from five patients with genetically defined IPD with disease-causing variants in WAS , RBM8A , FERMT3 , P2YR12 , and MYH9 served as controls during the validation process. In 40% of 35 patients analyzed, we were able to finally detect 15 variants, eight of which were novel, in 11 genes, ACTN1 , AP3B1 , GFI1B , HPS1 , HPS4 , HPS6 , MPL , MYH9 , TBXA2R , TPM4 , and TUBB1 , and classified them according to current guidelines. Apart from seven variants of uncertain significance in 11% of patients, nine variants were classified as likely pathogenic or pathogenic providing a molecular diagnosis for 26% of patients. This report also emphasizes on potentials and pitfalls of this tool and prospectively proposes its rational implementation within the diagnostic algorithms of IPD.
Highlights
Inherited platelet disorders (IPD) form a rare and heterogeneous disease entity that is present in about 8% of patients with non-acquired bleeding diathesis and characteristically associated with mucocutaneous bleeding episodes of variable intensity that may culminate in life-threatening hemorrhage during or after invasive procedures.[1,2,3] Impaired transcription regulation, receptor signaling, cytoskeleton formation, granule composition, or trafficking in megakaryocytes or platelets may result in a reduced circulating platelet count, platelets failing to fulfil their hemostatic function, or even a combined quantitative and qualitative platelet defect.[1]
Both sequencing procedure and data processing including in silico filtering exactly confirmed the known mutations and copy number variations (CNV) in the five genes leading to distinct phenotypes: adenosine diphosphate (ADP) receptor defect, leukocyte-adhesion deficiency type III, MYH9-related macrothrombocytopenia, thrombocytopenia-absent radius (TAR) syndrome, and Wiskott-Aldrich syndrome, respectively (►Supplementary Table S2)
Fifteen out of the 35 DNA samples (43%) revealed one or more genetic variants in the tested 59 genes that could be classified as class 3 or higher following in silico assessment
Summary
Inherited platelet disorders (IPD) form a rare and heterogeneous disease entity that is present in about 8% of patients with non-acquired bleeding diathesis and characteristically associated with mucocutaneous bleeding episodes of variable intensity that may culminate in life-threatening hemorrhage during or after invasive procedures.[1,2,3] Impaired transcription regulation, receptor signaling, cytoskeleton formation, granule composition, or trafficking in megakaryocytes or platelets may result in a reduced circulating platelet count, platelets failing to fulfil their hemostatic function, or even a combined quantitative and qualitative platelet defect.[1]. That are involved in either quantitative or qualitative platelet disorders, has increased rapidly and costs of high-throughput sequencing (HTS) technologies have declined simultaneously over the last decade, molecular genetic diagnosis of bleeding and platelet disorders (BPDs) is getting more and more valuable in diagnostic algorithms.[13,14,15]
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