Clinical phenotypic and genotypic analysis of Gitelman syndrome in children

Clinical phenotypic and genotypic analysis of Gitelman syndrome in children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical phenotypic and genotypic analysis of Gitelman syndrome in children Xingyu Yu, Zhefeng Yao, Lining Zhang, Xinyu Kuang, Lei Sun, Wenyan Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8174411/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Gitelman syndrome (GS) is a rare autosomal recessive tubulopathy caused by SLC12A3 mutations, leading to hypokalemic metabolic alkalosis and other electrolyte disturbances. This study aimed to investigate the genotype and clinical phenotype in pediatric patients with GS. Methods This retrospective study enrolled 29 pediatric patients from 2012 to 2022 in China. The clinical data and whole-exome sequencing results were collected. Functional validation of the novel SLC12A3 variant N227S was conducted using in vitro assays, including cell culture, plasmid transfection, RT-PCR, and Western blot. Results The initial manifestations were short stature, respiratory symptoms, and fatigue. Hypomagnesemia was present in 15 patients (51.7%), while 14 (48.3%) had normal serum magnesium levels. Serum magnesium correlated negatively with bicarbonate (r=-0.387, P=0.038), and children with hypomagnesemia had lower body weight (χ²=6.371, P=0.046). Missense mutations were most frequent (46.8%), with T60M being the most common (7.8%). Eight novel SLC12A3 variants were identified. Patients with splicing mutations had higher base excess (BE) and bicarbonate levels (t=-2.268, P=0.032 and t=-2.521, P=0.018, respectively). Functional studies showed that the N227S variant caused significant downregulation of SLC12A3 mRNA and Na+-Cl- cotransporter (NCC) protein expression, confirming its pathogenicity. Conclusions Pediatric GS often presents insidiously, and nearly half of patients do not exhibit hypomagnesemia, increasing the risk of misdiagnosis or delayed diagnosis. Splicing variants may be associated with more severe alkalosis. Eight novel SLC12A3 variants were identified, and the pathogenicity of the N227S variant was confirmed for the first time. Gitelman syndrome SLC12A3 Children Genotype–phenotype correlation Mutation Full Text Supplementary Files VisualAbstract.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8174411","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":550885898,"identity":"7ec6b62a-4e27-4e46-b9cf-13566621d676","order_by":0,"name":"Xingyu 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Mutation","lastPublishedDoi":"10.21203/rs.3.rs-8174411/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8174411/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\n\nGitelman syndrome (GS) is a rare autosomal recessive tubulopathy caused by SLC12A3 mutations, leading to hypokalemic metabolic alkalosis and other electrolyte disturbances. This study aimed to investigate the genotype and clinical phenotype in pediatric patients with GS.\n\nMethods\n\nThis retrospective study enrolled 29 pediatric patients from 2012 to 2022 in China. The clinical data and whole-exome sequencing results were collected. Functional validation of the novel SLC12A3 variant N227S was conducted using in vitro assays, including cell culture, plasmid transfection, RT-PCR, and Western blot.\n\nResults\n\nThe initial manifestations were short stature, respiratory symptoms, and fatigue. Hypomagnesemia was present in 15 patients (51.7%), while 14 (48.3%) had normal serum magnesium levels. Serum magnesium correlated negatively with bicarbonate (r=-0.387, P=0.038), and children with hypomagnesemia had lower body weight (χ²=6.371, P=0.046). Missense mutations were most frequent (46.8%), with T60M being the most common (7.8%). Eight novel SLC12A3 variants were identified. Patients with splicing mutations had higher base excess (BE) and bicarbonate levels (t=-2.268, P=0.032 and t=-2.521, P=0.018, respectively). Functional studies showed that the N227S variant caused significant downregulation of SLC12A3 mRNA and Na+-Cl- cotransporter (NCC) protein expression, confirming its pathogenicity. \n\nConclusions\n\nPediatric GS often presents insidiously, and nearly half of patients do not exhibit hypomagnesemia, increasing the risk of misdiagnosis or delayed diagnosis. Splicing variants may be associated with more severe alkalosis. Eight novel SLC12A3 variants were identified, and the pathogenicity of the N227S variant was confirmed for the first time.","manuscriptTitle":"Clinical phenotypic and genotypic analysis of Gitelman syndrome in children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 06:58:31","doi":"10.21203/rs.3.rs-8174411/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb4e353b-51aa-4a95-aaac-0add2ffc7b61","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T10:44:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 06:58:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8174411","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8174411","identity":"rs-8174411","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}