Abstract
Background
This study aimed to analyze genotype–phenotype correlations in children with Gitelman syndrome (GS).
Methods
This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient.
Results
The median age at the diagnosis was 10.5 years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4 years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those (n = 12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2 ± 3.2 vs. 96.5 ± 3.8 mMol/L, P = 0.002) at onset, as well as lower serum potassium levels (3.0 ± 0.4 vs. 3.4 ± 0.3 mMol/L, P = 0.016), and lower serum chloride levels (96.1 ± 1.9 vs. 98.3 ± 3.0 mMol/L, P = 0.049) during follow-up than those without truncating variants (n = 22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants.
Conclusions
Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants.
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References
Blanchard A, Bockenhauer D, Bolignano D, Calò LA, Cosyns E, Devuyst O, et al. Gitelman syndrome: consensus and guidance from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int. 2017;91(1):24–33.
Fulchiero R, Seo-Mayer P. Bartter syndrome and Gitelman syndrome. Pediatr Clin N Am. 2019;66(1):121–34.
Balavoine AS, Bataille P, Vanhille P, Azar R, Noël C, Asseman P, et al. Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome. Eur J Endocrinol. 2011;165(4):665–73.
Liu T, Wang C, Lu J, Zhao X, Lang Y, Shao L. Genotype/phenotype analysis in 67 Chinese patients with Gitelman’s syndrome. Am J Nephrol. 2016;44(2):159–68.
Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB. Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int. 2001;59(2):710–7.
Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996;12(1):24–30.
Shen Q, Chen J, Yu M, Lin Z, Nan X, Dong B, et al. Multi-centre study of the clinical features and gene variant spectrum of Gitelman syndrome in Chinese children. Clin Genet. 2021;99(4):558–64.
Vargas-Poussou R, Dahan K, Kahila D, Venisse A, Riveira-Munoz E, Debaix H, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol. 2011;22(4):693–703.
Zhang L, Huang K, Wang S, Fu H, Wang J, Shen H, et al. Clinical and genetic features in 31 serial Chinese children with Gitelman syndrome. Front Pediatr. 2021;9: 544925.
Viering D, Hureaux M, Neveling K, Latta F, Kwint M, Blanchard A, et al. Long-read sequencing identifies novel pathogenic intronic variants in Gitelman syndrome. J Am Soc Nephrol. 2023;34(2):333–45.
Rossanti R, Horinouchi T, Sakakibara N, Yamamura T, Nagano C, Ishiko S, et al. Detecting pathogenic deep intronic variants in Gitelman syndrome. Am J Med Genet A. 2022;188(9):2576–83.
Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr. 1997;131(2):252–7.
Kim JH, Yun S, Hwang SS, Shim JO, Chae HW, Lee YJ, et al. The 2017 Korean national growth charts for children and adolescents: development, improvement, and prospects. Korean J Pediatr. 2018;61(5):135–49.
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629–37.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.
Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, et al. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007;18(4):1271–83.
Berry MR, Robinson C, Karet Frankl FE. Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements. Nephrol Dial Transpl. 2013;28(6):1533–42.
Lemmink HH, Knoers NV, Károlyi L, van Dijk H, Niaudet P, Antignac C, et al. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int. 1998;54(3):720–30.
Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40(5):592–9.
Schlingmann KP, de Baaij JHF. The genetic spectrum of Gitelman(-like) syndromes. Curr Opin Nephrol Hypertens. 2022;31(5):508–15.
Zelikovic I, Szargel R, Hawash A, Labay V, Hatib I, Cohen N, et al. A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int. 2003;63(1):24–32.
Nagano C, Nozu K, Morisada N, Yazawa M, Ichikawa D, Numasawa K, et al. Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases. Clin Exp Nephrol. 2018;22(4):881–8.
Kondo A, Nagano C, Ishiko S, Omori T, Aoto Y, Rossanti R, et al. Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases. Sci Rep. 2021;11(1):16099.
Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jönsson A, et al. Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet. 2008;17(3):413–8.
Blanchard A, Vallet M, Dubourg L, Hureaux M, Allard J, Haymann JP, et al. Resistance to insulin in patients with Gitelman syndrome and a subtle intermediate phenotype in heterozygous carriers: a cross-sectional study. J Am Soc Nephrol. 2019;30(8):1534–45.
Wan X, Perry J, Zhang H, Jin F, Ryan KA, Van Hout C, et al. Heterozygosity for a pathogenic variant in SLC12A3 that causes autosomal recessive Gitelman syndrome is associated with lower serum potassium. J Am Soc Nephrol. 2021;32(3):756–65.
Filippatos TD, Rizos CV, Tzavella E, Elisaf MS. Gitelman syndrome: an analysis of the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities. Int Urol Nephrol. 2018;50(1):91–6.
Lorenz JN, Weihprecht H, Schnermann J, Skøtt O, Briggs JP. Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport. Am J Physiol. 1991;260(4 Pt 2):F486–93.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C1100974).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee at which the studies were conducted (IRB approval number HALLYM 2021–09-001) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Cho, M.H., Park, P.G., Kim, J.H. et al. Genotype–phenotype correlations in children with Gitelman syndrome. Clin Exp Nephrol (2024). https://doi.org/10.1007/s10157-024-02474-x
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DOI: https://doi.org/10.1007/s10157-024-02474-x