Reflections on the CAP+40-+43(-AAAC) mutation in β-thalassemia screening

Genetic screening for the CAP+40-+43 (-AAAC) mutation within the 5' untranslated region of the Hemoglobin Subunit Beta(HBB) gene is a typical component of β-thalassemia prevention and diagnosis. This mutation is known for its unpredictable phenotypic expression and controversial pathogenicity. This review comprehensively synthesizes decades of research, analyzing the genetic and clinical implications of the CAP+40-+43 (-AAAC) mutation and elucidating its underlying molecular mechanisms. We conducted an extensive literature review from 1980 to 2024, using PubMed and Chinese databases, focusing on all studies related to this specific mutation, including epidemiological surveys, case studies, and recent genetic findings. The results from populations in mainland China and Taiwan suggest that the CAP+40-+43 (-AAAC) mutation should not be considered inherently pathogenic but may contribute to variability in disease phenotype among individuals. Further detailed research is needed to better understand its role in β-thalassemia. Future studies should aim to identify the exact molecular pathways influenced by this mutation and develop intervention strategies that could alleviate its clinical impact, thus enhancing our comprehensive understanding of its biological significance. •Comprehensive review of the CAP+40-+43 (-AAAC) mutation in the HBB gene, synthesizing researches on its genetic and clinical implications.•Analyzes the phenotypic expression and controversial pathogenicity of the mutation in β-thalassemia.•Collects epidemiological data from mainland China and Taiwan, suggesting that the mutation should not be considered inherently pathogenic, but it may contribute to the variability of disease phenotype .•Emphasizes the need for further research to clarify the molecular mechanisms and clinical implications of the mutation.