Additive effect of multiple genetic variants in SEC23B and PIEZO1 on iron metabolism dyshomeostasis in hereditary anemias

Abstract Hereditary anemias encompass a genetically heterogeneous spectrum of disorders, often involving multi‐locus inheritance, which can complicate clinical management and worsen disease severity. This study investigates the impact of the co‐inheritance of SEC23B loss‐of‐function pathogenic variants, which lead to congenital dyserythropoietic anemia type II (CDA II), and PIEZO1 gain‐of‐function pathogenic variants, associated with dehydrated hereditary stomatocytosis type I (DHS1), on hematological parameters and iron metabolism. Among 583 patients with suspected hereditary anemia, 13 were found to carry both SEC23B and PIEZO1 variants, leading to a dual diagnosis of CDA II and DHS1. Compared to those with isolated CDA II, these patients exhibited a significantly higher absolute reticulocyte count and bone marrow responsiveness index, alongside an increased prevalence of elevated ferritin levels. Functional studies in Hep3B human hepatoma cells confirmed that SEC23B knockdown combined with PIEZO1 gain‐of‐function led to marked ferritin accumulation and reduced hepcidin expression, driven by altered BMP/SMAD signaling and ERK1/2 MAPK pathway. These findings demonstrate how multi‐locus inheritance can modify disease severity, particularly by exacerbating iron overload. Our results underscore the clinical relevance of comprehensive genetic testing for enhanced risk stratification and personalized management of hereditary anemias.