Clinical and Molecular Spectrum of Inherited Hemolytic Anemia Associated with Recurrent SPTB Variants and KLF1 Mutations in Northeastern Thailand

Abstract

Background: Inherited hemolytic anemia (IHA) caused by red cell membrane and erythroid transcription factor defects remains underrecognized in Northeastern Thailand. We aimed to describe the clinical spectrum, molecular findings and transfusion outcomes of pediatric IHA at a regional tertiary care center. Methods: We conducted a prospective cohort study at Maharat Nakhon Ratchasima Hospital from 2023 to 2025. Twenty-nine children with clinically suspected inherited hemolytic anemia were enrolled. Clinical features, hematologic parameters, transfusion history and family studies were reviewed. Common SPTB variants, including Providence c.6055T>C, Buffalo c.6074T>G and Chiang Mai c.6224A>G, were tested using multiplex ARMS-PCR with high-resolution melting analysis. KLF1 testing was performed in selected cases. Results: SPTB variants were identified in 22 of 29 patients. Hereditary pyropoikilocytosis (HPP) was the most common phenotype and was associated with homozygous or compound heterozygous SPTB variants, particularly Buffalo-containing genotypes. Most patients with HPP had severe neonatal-onset anemia, transfusion dependency and frequent perinatal complications, including hydrops fetalis. Patients with hereditary elliptocytosis and heterozygous SPTB variants had mild, non-transfusion-dependent disease. Two patients had compound KLF1 variants and transfusion-dependent anemia, one of whom had confirmed neonatal-onset disease. Most affected families were from Nakhon Ratchasima Province. Conclusion: Recurrent SPTB variants, particularly the Buffalo variant, were frequently identified among children with suspected IHA referred to our center and were associated with severe HPP phenotypes. Early molecular diagnosis may facilitate accurate classification, counseling and timely management.