Β-Thalassemia Gene Mutations With Normal Hematological Indices & Normal Hemoglobin Pattern in Jordan; Implications for Screening Programs: A Systematic Review and Meta-Analysis

Background: β-Thalassemia is prevalent in Jordan and the broader Eastern Mediterranean region. Routine carrier screening relies on red blood cell indices and hemoglobin pattern Analysis ; however, silent or mild β-thalassemia mutations can present with normal hematological parameters and HbA₂ levels, leading to under-detection. Objective: This systematic review and meta-analysis aimed to identify β-thalassemia mutations associated with normal hematological indices and normal hemoglobin patterns in Jordan and comparable populations, and to assess implications for national screening programs. Methods: We performed a comprehensive literature search in PubMed, PMC, and regional databases up to January 2026. Studies were included if they reported molecularly confirmed β-thalassemia carriers with normal mean corpuscular volume (MCV ≥80 fL), mean corpuscular hemoglobin (MCH ≥27 pg), and normal or borderline HbA₂. Data was extracted on mutation type, prevalence, hematological parameters, and screening outcomes. Due to heterogeneity, qualitative synthesis and random-effects meta-analysis were applied. Results: Evidence indicates that a substantial proportion of β-thalassemia carriers exhibit normal red cell indices and HbA₂ levels, evading conventional phenotypic screening (Weatherall & Clegg, 2001; Galanello & Origa, 2010). In Jordan, common silent or mild variants include IVS-I-6 (T>C), IVS-I-110 (G>A), IVS-II-745 (C>G), and promoter-region variants −101 (C>T) and −87 (C>G). Globally, additional silent alleles such as −92 (C>T) and CAP +1 (A>C) contribute to under-detection (Giambona et al., 2009; Old, 2003). These findings highlight the limitations of screening based solely on hematological indices and electrophoresis. Conclusions: Routine phenotype-based screening in Jordan may fail to identify silent β-thalassemia carriers. Integrating molecular diagnostics into screening programs can improve carrier detection, enable informed counseling, and strengthen preventive strategies.