An Evaluation for the Causes of Reduced Hb A₂ and the Molecular Characterization of HBD Variants in Hong Kong

Abstract

Prenatal screening of β-thalassemia (β-thal) carriers is based on the hallmark phenotype of microcytosis and raised Hb A₂. 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 HBD variants. In a broader sense, the causes of reduced Hb A₂ 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 A₂ levels (2.0%) were evaluated. HBD variations were assessed by direct sequencing. Sixty-six samples were tested. Hb H disease, HBD 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 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 A₂ in clinical practice and identified hereditary disorders of α- and δ-globin genes as the prevailing causes. It established the landscape of HBD variations in our locality and highlighted the pitfall of phenotypic screening of β-thal carriers.

Keywords:

• α-Thalassemia (α-thal)
• β-thalassemia (β-thal)
• δ-thalassemia (δ-thal)
• Hb A₂
• prenatal screening

Acknowledgements

We thank Ms. Kitman Chan (Department of Pathology, Alice Ho Miu Ling Nethersole Hospital, Taipo, Hong Kong) and Ms. Connie Wong (Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Shatin, Hong Kong), for screening the samples for recruitment.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This study was supported by the Chinese Thalassemia Foundation by Grant #2015/01.