Abstract
α-thalassemia is an inherited blood disorder commonly caused by deletions or point mutations involving one or both α-globin genes. Recent studies shed new light on the critical role of upstream enhancers multi-species conserved sequences (MCSs) in the ordered regulation of α-globin gene expression. Herein, we reported two unrelated probands with deletions in α-globin genes and MCSs, respectively. The proband from Family A is a compound heterozygote carrying a known α+ mutation (-α3.7) and a novel 60.2 kb deletion causing the absence of both α-globin genes. The proband from Family B, on the other hand, is a compound heterozygote with a known α0 mutation (--SEA) and a novel deletion involving only upstream regulatory elements MCS-R1, R2 and R3, while the α-globin genes remain intact. Notably, both these two patients suffered varied extent of anemia, indicating that the loss of enhancer elements could equally lead to reduced synthesis of α-globin. Upon these observations, we then confirmed the exact breakpoints of these two novel deletions using a targeted next-generation sequencing (NGS) previously established by our group, which may enable further elucidation of the rearrangement mechanisms on these deletions and functional dissection of MCSs. Taken together, our study reports a reliable NGS-based molecular screening approach for accurate identification of copy number variations (CNVs) in the α-globin cluster and the genetic diagnosis of these two probands may help to extend the spectrum of α-thalassemia mutations in Chinese population.
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Acknowledgements
We thank Mingli Xu for assistance in performing the experiments; we thank Sumin Zhao for assistance with data analysis. This research was supported by National Key R&D Program of China (2018YFA0507800 and 2018YFA0507803), Natural Science Foundation of China (81870148), Natural Science Foundation of Guangdong Province (2017A030313673), and Guangxi health and family planning commission self-funding project (Z20170528).
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Li, Z., Shang, X., Luo, S. et al. Characterization of two novel Alu element-mediated α-globin gene cluster deletions causing α0-thalassemia by targeted next-generation sequencing. Mol Genet Genomics 295, 505–514 (2020). https://doi.org/10.1007/s00438-019-01637-w
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DOI: https://doi.org/10.1007/s00438-019-01637-w