A Novel 165 Kb Duplication Involving the α-Globin Gene Cluster Is Identified by Low-Pass Whole Genome Sequencing in a Chinese Thalassemia Intermedia Patient

Abstract

Copy number variations (CNVs) involving the α-globin gene cluster can lead to an imbalance in the proportion of α- and β-globin chains and consequently cause clinical symptoms of β-thalassemia. In our case, a 6-year-old boy, clinically diagnosed with β thalassemia intermedia, was admitted for further genetic diagnosis with his family. Targeted sequencing and third generation sequencing (TGS) were used to detect the possible variants of the thalassemia genes. Low-pass whole genome sequencing (lpWGS) was conducted to specify the exact location of relevant CNVs across the genome, which was then validated by multiplex ligation-dependent probe amplification.The results revealed that the patient had a heterozygous β⁰ mutation of Codon17 (A > T) and a full duplication of the α-globin gene cluster, inherited from his mother and father, respectively. Besides, a novel point mutation within the 5′ untranslated region of β-Globin (HBB: c. −175 (G > A) was only detected in the patient. This study suggests that lpWGS seems a powerful alternative to detect large CNVs related to thalassemia with second intention for more information of the breakpoints and a simultaneous genome-scale detection of other pathogenic CNVs.

Keywords:

• β-thalassemia
• α-globin gene
• CNV
• lp WGS

Acknowledgements

The authors would like to thank Dr. Dongzhi Li and Dr. Fan Jiang from Guangzhou Women and Children Medical Center affiliated to Guangzhou Medical University for the MLPA validation; Dr. Lipei Liu from BGI-Tianjin Co.,Ltd for the analysis of low-pass whole genome sequencing results.

Authorship contribution statement

Xiaohong He: Resources, Writing-original draft, Funding acquisition. Peirun Tian: Formal analysis, Writing-original draft, Writing-Review & Editing. Shanshan Peng: Investigation. Lei Pan: Data Curation.Shiping Chen: Methodology. Lijuan Zhong: Visualization.Yutao Du: Supervision, Project administration.Rui Zhang: Conceptualization, Writing - Review & Editing, Funding acquisition.

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 work was supported by Shenzhen Key Medical Discipline Construction Fund (SZXK028) and Basic research project in Science and Technology program of Baoan District (20190509130643445).