Abstract Number: PB1514
Meeting: ISTH 2020 Congress
Background: Inherited platelet disorders (IPD) comprise rare and heterogeneous disorders. Despite extensive platelet function analysis, many patients with bleeding disorders remain without substantiated diagnosis. However, correct classification of the underlying genetic cause is essential for optimal treatment and genetic counseling.
Aims: We applied a panel-based next generation sequencing (NGS) approach based on an ISTH-based gene list to identify genetic variants in 38 IPD patients.
Methods: 59 genes known to be involved in platelet biogenesis or function were selected. Twenty-six children or adolescents and twelve adults were included into the study. Each patient had been evaluated in specialised centres due to a bleeding diathesis and considered to have a familial, syndromal or functionally diagnosed platelet disorder with early onset in life. Of these, 18 patients (47%) suffered from isolated thrombocytopenia, 16 (42%) from a platelet function disorder, and four from a combined defect (11%).
Results: For three patients, DNA quality was insuffucient for panel-analysis. In 40% of the remaining 35 analyzed patients, we detected 18 variants (phase#1 variant assessment in the 12 genes ACTN1, AP3B1, FLNA, GFI1B, HPS1, HPS4, HPS6, MPL, MYH9, TBXA2R, TPM4, and TUBB1), of which nine were novel. In 10 patients we found 13 variants of uncertain significance (VUS, class 3). Applying adequate functional tests and co-segregation analyses, 2 variants were attributed to be benign (class 1,2), 4 variants were reclassified as (likely) pathogenic (class 4,5). In total 9/35 patients received a definite genetic cause to their disease, providing a molecular diagnosis for 26% of patients.
Conclusions: This novel panel is capable of expanding genetic testing to patients that have failed standard approach to diagnosis following published guidelines, but requires accompanying functional tests and segregation analyses. We are currently updating the panel to the new ISTH gold standard.
To cite this abstract in AMA style:Schulze H, Manukjan G, Klopocki E, Andres O, GPOH/GTH Study Group 'ThromKid-Plus' on Inherited Platelet Disorders . Targeted High-throughput Sequencing for Genetic Classification of Patients with Inherited Platelet Disorders [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/targeted-high-throughput-sequencing-for-genetic-classification-of-patients-with-inherited-platelet-disorders/. Accessed October 2, 2023.
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