Inherited Thrombocytopenias Predisposing to Hematologic Neoplasms. Experience of the Spanish Group for Inherited Platelet Disorders (GEAPC)

Introduction In inherited thrombocytopenic disorders (IT) associated with germline genetic variants in the transcription factors RUNX1 (RUNX1-RT) and ETV6 (ETV6-RT) or ankyrin 26 (ANKRD26-RT), bleeding is usually not clinically relevant. However, patients have a high risk (10-45%) of developing hematologic malignancies (HM). Genetic diagnosis at an early stage of life is essential for these patients and their families, as the underlying genotype determines the natural history of the disease and, consequently, its prognosis and clinical management. High-Throughput Sequencing (HTS) has greatly facilitated diagnosing and providing personalized medicine for these patients. Objective The aim of this study was to evaluate the frequency, clinical characteristics, platelet phenotype and molecular alterations of patients with IT predisposing to HM, within the series of IT patients recruited by the Spanish Group of Inherited Platelet Disorders (GEAPC). Methods Since 2008, we have enrolled 296 patients (174 families) suspected of having any type of IT. They were selected according to their clinical and biological background. Bleeding (bleeding score (BS); ISTH-BAT), complete blood count and smear, and in many patients platelet phenotyping (platelet aggregation (LTA), cytometry, microscopy, etc.) were performed. Sanger sequencing of candidate genes (until 2014) or HTS was used for genetic diagnosis of patients. Candidate genetic variants were classified in accordance with the ACMG/AMP criteria, also taking into account the adapted specifications for RUNX1. Results Genetic diagnosis was obtained in 208 patients (76.3%) (135 families), identifying 26 different types of IT. Thirty patients (17 families) had RUNX1-RT (14.4%), 16 (5 families) had ANKRD26-RT (7.7%) and 7 cases (4 families) had ETV6-RT (3.4%). In patients with RUNX1-RT, the median age at identification of cytopenia and at genetic diagnosis was 17 (0-56) and 27 (1-71) years, respectively. Mild-to-moderate thrombocytopenia (95x109 pl/L (15-142)) and mild bleeding (BS=2(0-12)) was observed in 89% of these patients. Of the 13 patients evaluated, 83.3% had a reduced LTA at 2µg/ml collagen and 80% had low levels of glycoprotein Ia (collagen receptor). We identified 15 different variants in RUNX1 (8 novel); 47% missense, 30% nonsense, 12% large deletions, 6% splicing and 6% frameshift. Sixty-five percent of the variants were classified as pathogenic (PV), 6% as likely pathogenic (LPV), and 29% of uncertain signific