An Evaluation for the Causes of Reduced Hb A and the Molecular Characterization of Variants in Hong Kong.

Prenatal screening of β-thalassemia (β-thal) carriers is based on the hallmark phenotype of microcytosis and raised Hb A. The unanticipated birth of β-thal major (β-TM) offspring to β-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 variants. In a broader sense, the causes of reduced Hb A in thalassemia screening, the prevalence and spectrum of 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 levels (2.0%) were evaluated. variations were assessed by direct sequencing. Sixty-six samples were tested. Hb H disease, variants, α-thalassemia (α-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 variants were detected and two were recurrent, including : c.-127T>C [-77 (T>C)] and : c.314G>A (Hb Chori-Burnaby). A novel nonsense variant : c.262C>T [codon 87 (C>T)] was detected in with : c.-127T>C. Overall, the prevalence of variants was 0.4%. This study advanced our understanding of the causes of reduced Hb A in clinical practice and identified hereditary disorders of α- and δ-globin genes as the prevailing causes. It established the landscape of variations in our locality and highlighted the pitfall of phenotypic screening of β-thal carriers.