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Identification of new mutations in patients with hereditary spherocytosis by next-generation sequencing

Journal of Human Genetics volume 65, pages 427–434 (2020)Cite this article

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Abstract

Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear, hemolysis, splenomegaly, jaundice, and gallstones. To date, mutations in at least five genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB) have been found to be associated with different subtypes of HS. Here, we aim to investigate the presence of novel as well as known mutations in 35 Chinese patients with clinically suspected HS. Whole-exome sequencing (WES) has identified 3 patients with SLC4A1, 16 patients with ANK1, and 16 patients with SPTB mutations, including 5 splicing, 12 nonsense, 9 frameshift, 7 missense, and 1 start-loss mutation, indicating that SPTB and ANK1 are the most frequently mutated genes in Chinese HS patients. Among 34 mutations identified, 21 were novel. Most of SPTB and ANK1 mutations were nonsense (8/16) and frameshift (6/16) mutations. By trio analysis of eight families we have confirmed six de novo mutations. In addition, genotype–phenotype analysis was also performed by comparing clinical manifestations among three groups of patients with SPTB, ANK1, and SLC4A1 mutations. It revealed that patients with ANK1 mutations had a significantly higher level of MCV and MCH but lower percentage of spherocytes compared with those carrying SPTB mutations. In conclusion, our results suggested that molecular diagnosis by next-generation sequencing (NGS) is a fast, economic, and accurate way to detect and identify pathogenic alterations of inherited diseases, highlighting the potential usage of NGS in clinical practice.

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Acknowledgements

We appreciate the family members who participated in this study. This work was supported by the National Natural Science Foundation of China (grant number 81803562 and 81700115), Major Special Projects of Tianjin Science and Technology Service (grant number 17ZXFWGX00110), and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant number 2017-I2M-3-018).

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Authors and Affiliations

  1. Department of Pathology and Lab Medicine, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, PR China

    Li Qin, Donglei Zhang, Yani Lin & Kun Ru

  2. Tianjin Sino-US Diagnostics Co., Ltd., Tianjin, PR China

    Li Qin, Yanbo Nie, Hong Zhang, Long Chen, Donglei Zhang, Yani Lin & Kun Ru

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  1. Li Qin
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Correspondence to Kun Ru.

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Qin, L., Nie, Y., Zhang, H. et al. Identification of new mutations in patients with hereditary spherocytosis by next-generation sequencing. J Hum Genet 65, 427–434 (2020). https://doi.org/10.1038/s10038-020-0724-z

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