DP040 | NOVEL GENETIC VARIANTS AND OLIGOGENIC MECHANISMS IN IDIOPATHIC ERYTHROCYTOSIS: A TARGETED NEXT-GENERATION SEQUENCING APPROACH

Idiopathic erythrocytosis (IE) includes a heterogeneous group of disorders defined by increased red cell mass without secondary causes or known clonal mutations. While advances in molecular diagnostics have uncovered variants in genes related to oxygen sensing, erythropoietin signaling, iron metabolism, and red blood cell physiology, many cases remain unexplained, suggesting a polygenic basis. In this study, we performed targeted next-generation sequencing (NGS) using a comprehensive gene panel in 21 patients with idiopathic or familial erythrocytosis, excluding JAK2-mutated neoplasms and secondary causes. All patients underwent clinical and laboratory evaluation, including oxygen saturation, blood gases, imaging, and P50 measurement. DNA from peripheral blood was sequenced using the xGen Exome Hyb Panel v2 and Illumina NextSeq 550. Data were aligned to GRCh38, and variants were called, filtered, and classified per ACMG/AMP guidelines. Potentially pathogenic missense variants were further assessed with in silico prediction tools, clinical databases, and protein structural modeling. NGS identified 23 heterozygous variants in genes involved in oxygen sensing (VHL), erythropoietin signaling (EPOR, SH2B3), iron metabolism (HFE, SLC40A1, ACO1), red cell hydration (PIEZO1), and redox regulation (CYB5R3). Notably, two VHL variants (p.Pro81Ser and p.Arg210Pro) were predicted to affect protein structure and oxygen-dependent erythropoietin control. Functionally relevant variants were also detected in PIEZO1, SLC40A1, ACO1, CYB5R3, and HBB (p.Asp100Asn). In several patients, multiple rare variants co-occurred, supporting an oligogenic or polygenic model. These findings emphasize the genetic complexity of IE and support the use of broad gene panels and structural modeling to improve diagnostic yield and guide personalized management.