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Thirteen novel CLCNKB variants and genotype/phenotype association study in 42 Chinese patients with Bartter syndrome type 3

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Abstract

Purpose

Analyze the genotype of 42 Chinese patients with Bartter syndrome type 3 (BS3) and investigate their correlation between genotype and phenotype.

Methods

Identify CLCNKB gene variants by the next-generation sequencing and the multiplex ligation-dependent probe amplification (MLPA), and then evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines.

Results

Thirty-six different variants in CLCNKB gene, including 13 novel ones, were found. The whole gene deletion of CLCNKB gene was the most frequent mutation (40%), and the rate of large deletions is up to 55%. Among 36 variants, six (c.1244T>A, c.1468G>A, c.849_851delCTT, c.359G>T, c.1052G>T, and c.1309G>A) and three (c.228A>C, c.1294_1295TA>CT, and c.1333T>G) variants were classified as “likely pathogenic variants” and “variants with uncertain significance (VUS),” respectively. The other 27 variants were classified as “pathogenic variants”. The most common symptoms included: growth retardation (38/42), polydipsia and polyuria (35/42), constipation (31/42), and vomiting (27/42). All patients presented with hypokalemia, hypochloremia, and metabolic alkalosis. The genotype and phenotype association study revealed that who had mutations probably resulting in complete loss of function of both alleles might have severer phenotype. After the treatment that based on indomethacin and potassium chloride, most patients could achieve obvious recovery of growth rate and restoration of hypokalemia.

Conclusions

The present study have found 36 variants of CLCNKB gene, including 13 novel ones, which enrich the human gene mutation database and provide valuable references to diagnosis, treatment, and the genetic counseling of Chinese population.

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Acknowledgements

We thank all subjects for their participation.

Funding

This study was funded by the by grants from the National Natural Scientific Foundation (81873594).

Author information

Authors and Affiliations

  1. Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, No. 5 Donghai Middle Road, Qingdao, 266071, PR China

    Yue Han, Hai Cheng, Sai Wang, Xiaomeng Shi, Zhiying Liu & Leping Shao

  2. Central Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China

    Yue Han, Xiangzhong Zhao, Sai Wang, Xiaomeng Shi, Zhiying Liu & Leping Shao

  3. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China

    Shihong Shao & Yi Lin

  4. Department of Nursing, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China

    Yanhua Lang

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  1. Yue Han
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Correspondence to Leping Shao.

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Han, Y., Cheng, H., Shao, S. et al. Thirteen novel CLCNKB variants and genotype/phenotype association study in 42 Chinese patients with Bartter syndrome type 3. Endocrine 68, 192–202 (2020). https://doi.org/10.1007/s12020-019-02156-9

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  • DOI: https://doi.org/10.1007/s12020-019-02156-9

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