Essential genetic modifiers and their measurable impact in a community-recruited population analysis for non-severe hemoglobin E/β-thalassemia prenatal genetic counseling

The study aimed to identify essential phenotype-modulating factors among the pre-existence of several important ones and clarify their measurable impact on the clinical severity of hemoglobin (Hb) E/β-thalassemia in a community-recruited population analysis. This prospective study was designed to compare modifiers between community- (less or no symptoms) and hospital-recruited individuals with Hb E/β-thalassemia. The formerly included couples previously assessed for prenatal thalassemia at-risk status at 42 community and 7 referral hospitals in Thailand through on-site investigations between June 2020 and December 2021. The control included Hb E/β-thalassemia patients undergoing transfusions. The Mahidol score classified disease severity. Beta-globin, α⁰-thalassemia (-^SEA, -^THAI), α⁺-thalassemia (-α^3.7, -α^4.2), Hb Constant Spring (α^CS) alleles, rs766432 in BCL11A, rs9399137 in HBS1L-MYB, and rs7482144-XmnI were evaluated. Modifiers were compared between 102 community- and 104 hospital-recruited cases. Alleles of β⁺, -^SEA, -α^3.7, α^CS, and a minor allele of rs9399137 were prevalent in the community and mild severity groups (p < 0.05). Multiple linear regression analysis associated modulating alleles with −4.299 (-^SEA), −3.654 (β⁺), −3.065 (rs9399137, C/C), −2.888 (α^CS), −2.623 (‐α^3.7), −2.361 (rs7482144, A/A), −1.258 (rs9399137, C/T), and −1.174 (rs7482144, A/G) severity score reductions (p < 0.05). Certain modifiers must be considered in routine prenatal genetic counseling for Hb E/β-thalassemia.