467 Hereditary predisposition syndrome for myelodysplastic syndrome with SF3B1 mutation; a case report

Introduction/Objective Somatic (acquired) mutations in SF3B1 are a defining characteristic of myelodysplastic syndrome (MDS) with low blasts, per the World Health Organization 2022 classification of hematolymphoid tumors; per the International Consensus Classification 2022 classification, a heterozygous SF3B1 mutation with a variant allele frequency (VAF) of > 10% is required for the diagnosis of MDS-SF3B1. Genetic (inherited) predisposition to MDS with mutations in other genes has also been reported. Methods/Case Report A 57-year-old Caucasian male had been followed up at an outpatient medical center due to persistent and progressive iron overload, stomatocytosis, and macrocytosis. He had a family history of chronic macrocytic anemia in his mother and sister. Bone marrow studies at 51 years of age were normal, showing no dyspoiesis or ring sideroblasts. Four years later, due to the finding of a PIEZO1 variant of unknown significance, the patient along with his mother and sister were enrolled in an IRB-approved diagnostic research study and had whole genome sequencing (WGS)-trio that showed two somatic gene variants: SF3B1 p.K700E and TET2 c.2171_2178del, p.H724R*27 (with VAF of 33% and 17%, respectively), confirmed with Sanger sequencing. A repeat bone marrow examination revealed MDS with low blasts and ring sideroblasts. Molecular tests confirmed the mutations SF3B1 K700E, and TET2 H724R*27. Acquired SF3B1 K700E mutation was also identified by the WGS-trio in the patient’s mother and sister, albeit in lower VAF. None of the known genes reported to cause hereditary predisposition to MDS were identified in the family but a novel CDC25A c.430-2A>T het was shared at VAF ∼50% which is proposed as a candidate gene variant causing hereditary macrocytosis and predisposition to MDS-SF3B1. Results NA Conclusion Although mutations in some genes have been associated with inherited predisposition to MDS, to our knowledge, there has been no report of a case of hereditary MDS-predisposition syndrome with SF3B1 gene mutation. Herein, we present the first case of a hereditary MDS-predisposition syndrome with SF3B1 gene mutation. This report aimed to increase awareness regarding the possibility of hereditary MDS-predisposition syndrome in patients with MDS and SF3B1 mutation.