Pb2624: clinical whole exom sequencing for congenital platelet disorders: one single center experience

Topic: 32. Platelet disorders Background: Thrombocytopathies has been traditionally entities with few characterization laboratory tests and even fewer etiological diagnosis tools. New gene sequencing techniques may constitute a promising resource to identify some of the affected molecular pathways and consequently to establish a prognosis. One of them, clinical exome sequencing (Sophia Genetics), was used to sequence 4,728 genes associated with rare diseases and hereditary predisposition syndromes. Briefly, DNA was extracted and libraries were prepared using a capture-based assay. Aims: Evaluate the usefulness of clinical exome sequencing (CES) within the diagnostic algorithm of the congenital platelets disorders (CPD). Methods: After clinical, ISTH Bleeding Assessment Tool included, and either basic or specific laboratory evaluation, patients highly suspicious of thrombocytopathies in our Center were considered for clinical exome sequencing. Informed consent was given. Sequencing was performed in a NextSeq550 analyzer. The SOPHIA DDM platform was used for bioinformatics analysis. Pathogenic and likely pathogenic variants were called using Sophia’s filters and the ACMC classification. Manual curation and literature review was performed by an expert hematologist. Results: Between January 2020 and February 2023, there were performed CES in 26 patients, with an average age of 53 years, 73% of whom were women, and an average follow-up period of 8 years. We found 9 mutations described as pathogenic and concordant with the patient’s symptoms, some of them not previously described. Neither ISTH-BAT nor an inherited pattern were predictors of CES findings related with platelet disorders. Prolonged follow-up in consultations due to persistence of the symptomatology does seem to be relevant for the cost-effectiveness of the technique. Table 1: Characteristics of the patient with trhrombocytopathies who underwent CES in our center. (VWF: Von-Willebrand Factor, VF: Variant Frecuency, B-CCL: B-Chronic Lymphocytic Leukemia, MPN; Myeloproliferative Neoplasms, T-NHL: T- non-Hodgkin’s lymphoma, ITP: Immune Thrombocytopenia) Summary/Conclusion: CES is useful for typing congenital thrombocytopathies but a good clinical and temporal evaluation of the persistence of symptoms seems important for greater diagnostic yield. In our series, the possible hereditary pattern does not guarantee positive results in the study, the possible reasons being both bleeding diathesis not linked to platelets and functional thrombocytopathies not mediated by a single target in the platelet. Keywords: Inherited platelet disorders, Bernard-Soulier syndrome