Abstract Number: OC 21.4
Meeting: ISTH 2021 Congress
Background: Inherited platelet disorders are classified as rare diseases. However, since the upcoming focus for high-throughput sequencing in the diagnosis of thrombocytopenias and thrombocytopathies, a rising number of unknown variants are entering the databases. Coherent classification of the underlying genetic cause is of high relevance for appropriate prognosis, genetic counseling, and therapy.
Aims: To diagnose patients with inherited platelet disorders. Clinical signs and platelet function analyses were complemented by a next generation sequencing (NGS) approach according to the ISTH gold variant guideline.
Methods: NGS was initially panel-based and has been transferred to an in-silico panel applied to whole-exome data (Nextera-Library-Prep-Kit, Illumina; Nextera-xGen-Exome-Research-Panel, IDT). The ISTH Platelet Disorder TIER1 genes (v.ISTH_2020.1) are included in our analysis. Data analysis was performed by GensearchNGS (PhenoSystems, Wallonia, Belgium). Genetic variants were called for minor allele frequency (MAF), exon distance (±10 bp into intron), and quality (variant present in > 10% of the NGS reads, coverage > 5X). Twenty-nine patients that were evaluated between 2018 and 2020 in specialized centers due to a bleeding diathesis and considered having a familial, syndromal or functionally diagnosed platelet disorder with early onset in life, were included into the study. In case of clear clinical suspicion, patients were subjected to direct Sanger sequencing (5 WAS cases).
Results: In 14 patients we detected single nucleotide variants in: ACTN1; ANKRD26; HPS1; ITGA2B; ITGB3; MYH9; RASGRP2; WAS. For nine of those patients, variants were detected by NGS. According to ACMG criteria five variants were defined as pathogenic, four as likely pathogenic, and two as uncertain significance.
Conclusions: In a collection period of two years, we could identify the genetic cause of a broad range of clinically conspicuous platelet disorders by NGS with a positive testing ratio of 37.5 % (9/24 patients). Four newly defined variants, characterized as likely pathogenic, were added to the Gold Variant list.
To cite this abstract in AMA style:Schulze H, Manukjan G, Borst A, Klopocki E, Andres O, GPOH/GTH study group of Inherited Platelet Disorders . Identification of Novel Variants by Panel-based High-throughput Sequencing Associated with Platelet Function Disorders [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/identification-of-novel-variants-by-panel-based-high-throughput-sequencing-associated-with-platelet-function-disorders/. Accessed September 16, 2021.
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