An Evaluation for the Causes of Reduced Hb A(2) and the Molecular Characterization of HBD Variants in Hong Kong

Prenatal screening of beta-thalassemia (beta-thal) carriers is based on the hallmark phenotype of microcytosis and raised Hb A(2). The unanticipated birth of beta-thal major (beta-TM) offspring to beta-thal carriers who were misdiagnosed during prenatal screening have been reported. A subset of these resulted from the masked phenotype due to the coinheritance of HBD variants. In a broader sense, the causes of reduced Hb A(2) in thalassemia screening, the prevalence and spectrum of HBD variants in Hong Kong remain to be characterized. Over a 13-month period, a total of 2982 samples were referred for thalassemia screening. Surplus samples with reduced Hb A(2) levels (2.0%) were evaluated. HBD variations were assessed by direct sequencing. Sixty-six samples were tested. Hb H disease, HBD variants, alpha-thalassemia (alpha-thal) trait and iron deficiency were detected in 40 (60.6%), 12 (18.2%), eight (12.1%) and seven (10.6%) samples, respectively. Seven samples carried more than one of the mentioned conditions. The cause remained elusive in seven samples. Thirteen HBD variants were detected and two were recurrent, including HBD: c.-127T>C [-77 (T>C)] and HBD: c.314G>A (Hb Chori-Burnaby). A novel nonsense variant HBD: c.262C>T [codon 87 (C>T)] was detected in cis with HBD: c.-127T>C. Overall, the prevalence of HBD variants was 0.4%. This study advanced our understanding of the causes of reduced Hb A(2) in clinical practice and identified hereditary disorders of alpha- and delta-globin genes as the prevailing causes. It established the landscape of HBD variations in our locality and highlighted the pitfall of phenotypic screening of beta-thal carriers.