Case report: Identification of a novel triplication of alpha-globin gene by the third-generation sequencing: pedigree analysis and genetic diagnosis

ABSTRACT

Background

Thalassemia, a common autosomal hereditary blood disorder worldwide, mainly contains α- and β-thalassemia. The α-globin gene triplicates allele is harmless for carriers, but aggravates the phenotype of β-thalassemia. Therefore, it is particularly crucial to accurately detect the structural variants of α-globin gene clusters.

Case report

We reported a 28-year-old man, the proband, with microcytic hypochromic anemia. From pedigree analysis, his mother and sister had hypochromic microcytosis, and his father was normal. Genetic testing of thalassemia identified a novel α-globin gene triplicate named ααα^{anti4.2del726bp} (NC_000016.10:g.170769_174300dupinsAAAAAA) by third-generation sequencing (TGS) in the proband and his father, which was further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The genotypes of the proband’s mother and sister were both -α^3.7/αα compounded with heterozygous HBB:c.126_129delCTTT. They were categorized as silent α-thalassemia with co-inheritance of β-thalassemia trait. The proband’s genotype additionally had the α-globin gene triplicates compared with his mother and sister, which increased the imbalance between α/β-globin, so the proband had more severe hematological parameters. The proband’s wife was diagnosed as HBA2:c.427T > C heterozygosis, and his daughter had the novel α-globin gene triplicates compounded with HBA2:c.427T > C, therefore the girl might be asymptomatic.

Conclusion

The identification of the novel α-globin gene triplicates provides more insight for the research of thalassemia variants and indicates that TGS has significant advantages on genetic testing of thalassemia for the reliability, accuracy and comprehensiveness.

KEYWORDS:

• Thalassemia
• α-globin gene triplicates
• β-thalassemia
• breakpoint
• third-generation sequencing

Acknowledgements

The authors would like to thank the patients for their participation in this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

YC discovered the cases, collected and analyzed the data. TX analyzed the data and wrote the first draft of the manuscript, MM analyzed the data and provided the technical support, JY conducted genetic testing and analyzed the data. YL analyzed the data, DD designed the study, analyzed the data and reviewed the manuscript.

Ethics statement

The study was approved by the Clinical Ethics Committee of The First People’s Hospital of Yunnan Province. All procedures were performed in accordance with the Declaration of Helsinki and international and national guidelines for human studies. Informed written consent was obtained from all the subjects or their legal guardians.

Data availability statement

The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.

Additional information

Funding

This work was supported by Special training project for High-level health technical personnel of Yunnan province (No. L-2018006) and Clinical Research Center for Gynecological and Obstetric Disease of Yunnan Province (No. 2022YJZX-FC21). We would like to thank all the subjects for their participation in this study.