The molecular spectrum of alpha- and beta-thalassemia pathogenic variants in Indonesia: implications for national screening and prevention

Abstract

Thalassemia is classified globally as a rare disease; however, it represents a major public health burden in many low‑ and middle‑income countries due to its high prevalence and limited access to care. In Indonesia, one of the world’s most genetically diverse populations, thalassemia traits present epidemiological characteristics more consistent with a common disease than a rare one in certain populations. However, the national molecular spectrum of alpha‑ and beta‑thalassemia, essential for carrier screening and prevention programs, is still insufficiently characterized. Hematological screening (red cell indices and HbA₂ levels) remains the gold standard, but molecular diagnostics are required for definitive diagnosis and accurate carrier identification. This study analyzed archived data from 4,779 individuals across Western Island Southeast Asia and Eastern Island Southeast Asia collected between 1995 and 2016. Thalassemia screening was based on hematological criteria including MCV, RBC morphology, and HbA2 levels assessed via CBC and HPLC. For 180 whole-genome sequenced individuals, pathogenic variants in HBA1 / HBA2 and HBB genes were identified by cross-referencing ClinVar. Pathogenic variants were detected in 13.2% of subjects. Alpha‑thalassemia trait was dominated by the alpha 3.7 deletion, while beta‑thalassemia trait was primarily driven by HbE heterozygosity. Pathogenic variants frequencies varied markedly by region, with higher burdens in eastern Indonesia. Genotype‑specific hematological profiles highlighted the limitations of routine hematology for identifying mild or silent carriers. This broad analysis defines the molecular landscape of thalassemia traits in Indonesia and reveals substantial regional heterogeneity. These findings support the development of population‑tailored molecular diagnostic panels to improve carrier detection, enable earlier intervention, and strengthen equitable thalassemia prevention strategies in underrepresented populations. Integrating molecular diagnostics with hematological screening would create a more robust and equitable national strategy for thalassemia screening.