Genetic study of patients with Gitelman syndrome_West China Medical Journal

Authors：

SUN Yihong ^1,2 , WANG Xiaoshu ² , REN Yan ¹ , LU Chunyan ¹ , TIAN Haoming ¹ ,  CHEN Tao ¹

1. Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Endocrinology and Metabolism, Guang’an Hospital, West China Hospital, Sichuan University, Guang’an, Sichuan 638000, P. R. China;

Corresponding author：

CHEN Tao, Email: dr.chentao@qq.com

Keywords：

Gitelman syndrome; Hypokalemia; Hypomagnesemia

DOI：

10.7507/1002-0179.202001046

Video：

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Objective To screen pathogenic gene mutations of Gitelman syndrome (GS).Methods Patients with GS diagnosed and treated in the Department of Endocrinology and Metabolism, West China Hospital of Sichuan University from January 2015 to December 2020 and their family members were included. The pathogenic genes were screened by second-generation sequencing combined with first-generation validation.Results A total of 15 GS patients were included. Gene analysis of patients indicated SLC12A3 gene mutation, including 9 cases of compound heterozygous mutation and 6 cases of heterozygous mutation. A total of 12 reported pathogenic sites and 8 new pathogenic mutations were found. Among the newly discovered pathogenic mutations, four were missense mutations (c.539C>A, p.T180K; c.1077C>G, p.N359K; c.1967C>T, p.P656L; and c.2963T>C, p.I988T), one was frame shift mutation caused by single base deletion (c.2543delA, p.D848fs), one was nonsense mutation (c.2129C>A, p.S710X), one was large fragment deletion (exon 7-8 partial coding sequence deletion), and one was coding sequence deletion and abnormal base sequence insertion (IVS7-1 to c.976 deletion GCGGACATTTTTG insertion into ACCGAAAATTTT).Conclusion In this study, 8 new gene mutations leading to GS were found, and the exact pathogenesis of GS remains to be further confirmed.

Citation： SUN Yihong, WANG Xiaoshu, REN Yan, LU Chunyan, TIAN Haoming, CHEN Tao. Genetic study of patients with Gitelman syndrome. West China Medical Journal, 2021, 36(4): 488-492. doi: 10.7507/1002-0179.202001046 Copy

1.	Scognamiglio R, Calò LA, Negut C, et al. Myocardial perfusion defects in Bartter and Gitelman syndromes. Eur J Clin Invest, 2008, 38(12): 888-895.
2.	Scognamiglio R, Negut C, Calò LA. Aborted sudden cardiac death in two patients with Bartter’s / Gitelman’s syndromes. Clin Nephrol, 2007, 67(3): 193-197.
3.	Zhou H, Liang X, Qing Y, et al. Complicated Gitelman syndrome and autoimmune thyroid diease: a case report with a new homozygous mutation in the SLC12A3 gene and literature review. BMC Endocr Disord, 2018, 18(1): 82.
4.	Liu S, Ke J, Zhang B, et al. A novel compound heterozygous variant of SLC12A3 gene in a pedigree with gitelman syndrome co-existent with thyroid dysfunvtion. Endocr Pract, 2018, 24(10): 889-893.
5.	秦岭, 邵乐平, 任红, 等. 中国人Gitelman综合征高发突变的基因型和表型特征. 肾脏病与透析肾移植杂志, 2008, 17(4): 331-334.
6.	王芬, 崔云英, 李春艳, 等. 64例Gitelman综合征患者临床表现和基因突变分析. 基础医学与临床, 2017, 37(11): 1601-1606.
7.	Blanchard A, Bockenhauer D, Bolignano D, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int, 2017, 91(1): 24-33.
8.	彭晓燕, 蒋兰萍, 袁涛, 等. 氯离子清除试验在Gitelman综合征鉴别诊断中的应用. 中国医学科学院学报, 2016, 38(3): 275-282.
9.	Glaudemans B, Yntema HG, San-Cristobal P, et al. Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome. Eur J Hum Genet, 2012, 20(3): 263-270.
10.	Luo JW, Meng XR, Yang X, et al. Analysis of mutations of two Gitelman syndrome family SLC12A3 genes and proposed treatments using Chinese medicine. Chin J Integr Med, 2017, 23(6): 461-468.
11.	Ma J, Ren H, Lin L, et al. Genetic features of Chinese patients with Gitelman syndrome: sixteen novel SLC12A3 mutations identified in a new cohort. Am J Nephrol, 2016, 44(2): 113-121.
12.	Cruz Dn, Shaer AJ, Bia MJ, et al. Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int, 2001, 59(2): 701-717.
13.	Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalamic alkalosis, is caused by mutations in the thiazide-sensitive NA-Cl cotransporter. Nature Genet, 1996, 12(1): 24-30.
14.	14Vargas-Poussou R, Dahan K, Kahila D, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol, 2011, 22(4): 693-703.
15.	Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet, 2017, 100(2): 267-280.

1. Scognamiglio R, Calò LA, Negut C, et al. Myocardial perfusion defects in Bartter and Gitelman syndromes. Eur J Clin Invest, 2008, 38(12): 888-895.
2. Scognamiglio R, Negut C, Calò LA. Aborted sudden cardiac death in two patients with Bartter’s / Gitelman’s syndromes. Clin Nephrol, 2007, 67(3): 193-197.
3. Zhou H, Liang X, Qing Y, et al. Complicated Gitelman syndrome and autoimmune thyroid diease: a case report with a new homozygous mutation in the SLC12A3 gene and literature review. BMC Endocr Disord, 2018, 18(1): 82.
4. Liu S, Ke J, Zhang B, et al. A novel compound heterozygous variant of SLC12A3 gene in a pedigree with gitelman syndrome co-existent with thyroid dysfunvtion. Endocr Pract, 2018, 24(10): 889-893.
5. 秦岭, 邵乐平, 任红, 等. 中国人Gitelman综合征高发突变的基因型和表型特征. 肾脏病与透析肾移植杂志, 2008, 17(4): 331-334.
6. 王芬, 崔云英, 李春艳, 等. 64例Gitelman综合征患者临床表现和基因突变分析. 基础医学与临床, 2017, 37(11): 1601-1606.
7. Blanchard A, Bockenhauer D, Bolignano D, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int, 2017, 91(1): 24-33.
8. 彭晓燕, 蒋兰萍, 袁涛, 等. 氯离子清除试验在Gitelman综合征鉴别诊断中的应用. 中国医学科学院学报, 2016, 38(3): 275-282.
9. Glaudemans B, Yntema HG, San-Cristobal P, et al. Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome. Eur J Hum Genet, 2012, 20(3): 263-270.
10. Luo JW, Meng XR, Yang X, et al. Analysis of mutations of two Gitelman syndrome family SLC12A3 genes and proposed treatments using Chinese medicine. Chin J Integr Med, 2017, 23(6): 461-468.
11. Ma J, Ren H, Lin L, et al. Genetic features of Chinese patients with Gitelman syndrome: sixteen novel SLC12A3 mutations identified in a new cohort. Am J Nephrol, 2016, 44(2): 113-121.
12. Cruz Dn, Shaer AJ, Bia MJ, et al. Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int, 2001, 59(2): 701-717.
13. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalamic alkalosis, is caused by mutations in the thiazide-sensitive NA-Cl cotransporter. Nature Genet, 1996, 12(1): 24-30.
14. 14Vargas-Poussou R, Dahan K, Kahila D, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol, 2011, 22(4): 693-703.
15. Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet, 2017, 100(2): 267-280.

West China Medical Journal

Genetic study of patients with Gitelman syndrome

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