From gene to clinic: A single-center exploration of genotype-phenotype correlation in pediatric hereditary spherocytosis

INTRODUCTION: Hereditary spherocytosis (HS) is a genetically heterogeneous hemolytic anemia characterized by mutations in erythrocyte membrane protein genes such as ANK1, SPTB, SPTA1, SLC4A1, and EPB42. While genotype–phenotype associations have been partially described, the clinical variability remains insufficiently understood, particularly in pediatric populations. This study aimed to investigate genotype–phenotype correlations in Turkish children with HS.
METHODS: This retrospective study included 13 pediatric patients diagnosed with HS between 2020 and 2024 at a single tertiary care center. Genetic testing was performed using targeted next-generation sequencing (NGS). Clinical data including hemoglobin levels, reticulocyte counts, bilirubin levels, transfusion requirements, and history of splenectomy were analyzed in relation to identified variants.
RESULTS: Ten of 13 patients (77%) had pathogenic or likely pathogenic variants. Mutations in ANK1 were the most common, followed by SPTB and SLC4A1. Two novel variants were identified: a nonsense mutation in SPTB (p.Gln1578*) and a start-loss mutation in ANK1 (p.Met1Ile). Although the p.Met1Ile protein change has been previously reported, the nucleotide substitution (c.3G>A) identified in our study was novel. Clinical severity varied, even among patients carrying the same mutation.
DISCUSSION AND CONCLUSION: This study reinforces established genotype–phenotype trends in HS and highlights the value of molecular diagnosis in clinical risk assessment and management. Despite observed associations, significant phenotypic variability underscores the necessity of integrating genetic testing with clinical evaluation to optimize patient care.