Founder Mutation p.C421F in SLC12A3 Underlies the High Prevalence of Gitelman Syndrome in the Yi Population of China

Founder Mutation p.C421F in SLC12A3 Underlies the High Prevalence of Gitelman Syndrome in the Yi Population of China | 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 Founder Mutation p.C421F in SLC12A3 Underlies the High Prevalence of Gitelman Syndrome in the Yi Population of China Jian Han, Jinghua Gao, Lanxin Ma, Honghan Zhang, Ying Hu, Wenqian Zhao, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7109230/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 an autosomal recessive inherited renal tubular disorder, primarily caused by mutations in the SLC12A3 gene. Its prevalence varies significantly among different populations. Previous studies have found that the incidence rate in the Yunnan Yi community of China is notably higher. Factors such as the founder effect contribute to the unique genetic characteristics observed in isolated populations. This study aims to explore the genetic basis for the increased prevalence of GS in the Yi population, focusing on identifying common mutations in the SLC12A3 gene. Preliminary results suggest that the p.C421F variant may be a founder mutation in this population, which could enhance diagnostic strategies and inform public health initiatives. Methods All patients underwent WES, followed by family analysis and verification with Sanger sequencing.Sanger sequencing was used to detect the p.C421F mutation in 1,000 random volunteers from the Yi population. Haplotype analysis was conducted using PLINK software. Results The prevalence of GS in this region is approximately 1 in 1,000, with an allele frequency of 3% for the p.C421F mutation. All 19 GS patients were homozygous for the p.C421F mutation, and a common haplotype surrounding the p.C421F allele was identified in 17 of the GS patients, with a length of at least 499 kb. Conclusions Our study reports a higher prevalence of GS in the Yunnan Yi community and confirms that this phenomenon is due to the founder effect of the SLC12A3 gene p.C421F mutation. Figures Figure 1 Figure 2 Introduction Gitelman syndrome (GS, OMIM #263800), also referred to as familial hypokalemia and hypomagnesemia, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis 1 . It is caused by biallelic loss-of-function variants in the SLC12A3 gene (OMIM *600968) 2,3 The estimated prevalence of GS is approximately 1–10 per 40,000 individuals in Europe 2 , while in Japan, it may be as high as 10.3 per 10,000 individuals 4 . A study involving Chinese children reported a heterozygous SLC12A3 variant frequency of approximately 2.9% 5 . In another cohort of Chinese school-aged children (n = 500), the allele frequency of heterozygous SLC12A3 mutations was found to be 3% 6 , suggesting a potentially unique genetic predisposition in the Chinese population. However, comprehensive epidemiological data on the actual prevalence remains lacking 7 . It is noteworthy that when a small subgroup separates from a larger population and establishes a new community, certain genetic mutations present in the original population may become more prevalent in the new group due to genetic drift, leading to what is known as the founder effect 8 . The elevated mutation frequencies in geographically isolated populations often indicate the possible involvement of founder mutations. For instance, the exon 9–14 duplication (E9_E14dup) identified in individuals of Greek Cypriot descent has been recognized as a founder mutation among GS patients in that region 9 . This study reports a clustering of GS cases within a Yi ethnic community in Yunnan, China, based on the identification of two GS patients carrying the SLC12A3 c.1262G > T (p.C421F) mutation through population screening and case tracing. Moreover, haplotype analysis confirmed, for the first time, the presence of a founder mutation in this population. Methods A total of 1,000 volunteers were randomly recruited from a Yi ethnic community in Yunnan, China, to screen for the p.C421F mutation of SLC12A3 (ENST00000438926, NM_000339.3) using Sanger sequencing. The PCR primer sequences were as follows: forward: 5′-GATGCCTCTGGGGTCCTGAA-3′; reverse: 5′-TCGCAAAGGCACTGGAAGAC-3′. PCR amplification was followed by Sanger sequencing on an ABI 3500xL Dx Genetic Analyzer. Based on the sequencing results, pedigree investigations were conducted for individuals identified as heterozygous carriers and for families of patients diagnosed with GS. Whole-exome sequencing (WES) was performed on all patients diagnosed with GS by Sanger sequencing using the MGISEQ-2000 platform. Following quality control, 204,443 autosomal single nucleotide polymorphisms (SNPs) loci were retained for analysis. The Human GRCh38/hg38 assembly was used as the reference genome, and genotype imputation was conducted with Beagle 5. Haplotype analysis was conducted using PLINK. Preliminary quality control was performed in PLINK (minor allele frequency [MAF] > 0.01, missing rate < 5%), and haplotype blocks were defined based on linkage disequilibrium (LD) using the --blocks command. The pathogenicity of candidate variants was interpreted according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) 10 . Results Targeted sequencing for the p.C421F variant identified 55 heterozygous carriers and two individuals with GS among 1,000 participants, spanning 12 distinct families. Based on Hardy-Weinberg equilibrium, the estimated allele frequency of the variant was approximately 3%. Given a total population of approximately 20,000 in this region, the estimated local prevalence of p.C421F-associated GS is 1 in 1,000. Pedigree analysis of these 12 families ultimately identified 19 individuals affected by GS. WES confirmed that all patients were homozygous for the p.C421F mutation (Fig. 1 ). Haplotype analysis was conducted on 19 of the GS patients. LD analysis revealed a strong LD block surrounding the mutation site at Chr16:56913066 (Fig. 2 -A). Notably, 89.5% (n = 17/19) of the GS patients shared a common haplotype of at least 499 kb in length (Chr16:56686471–57185949) (Fig. 2 -B). Among the 19 identified GS patients, all (100%, n = 19/19) exhibited chronic hypokalemia (< 3.5 mmol/L) and hypomagnesemia (< 0.7 mmol/L). Fatigue was reported in 94.5% of patients (n = 18/19), while 89.5% (n = 17/19) had hypocalciuria and abnormal renin levels. Additionally, 10.5% of patients (n = 2/19) presented with abnormal fasting blood glucose and aldosterone levels. Additional clinical details are provided in Supplementary Table 1. Discussion In this study, we identified two probands with homozygous p.C421F mutations in SLC12A3 from a Yi ethnic community in Yunnan, China. Based on these findings, we recruited 1,000 local participants and performed targeted sequencing for the p.C421F variant, estimating its allele frequency to be approximately 3%. Pedigree analyses were then conducted among newly identified GS patients and heterozygous carriers. A total of 19 GS patients were identified across 12 families, all of whom were homozygous for the p.C421F mutation. These results indicate that the prevalence of GS attributable to the founder mutation of p.C421F in this population is approximately 1 in 1,000 11 . Given the potential presence of additional pathogenic variants in the SLC12A3 , we speculate that the actual prevalence of GS in this region may be higher than 1 in 1,000. This suggests that there may be underrecognized genetic factors contributing to the elevated prevalence of GS in East Asian populations. Moreover, a study based on genomic databases estimated the predicted prevalence of GS across various ethnic groups and found that the prevalence in the Japanese population, as well as in certain ethnicities, was higher than previously reported 12 . These findings suggest that the prevalence of GS in East Asian populations may have been substantially underestimated. The distribution of mutant alleles of the SLC12A3 demonstrates significant population heterogeneity 13 . In European populations, the predominant variants are R861C and L859P, whereas in Chinese populations, high-frequency mutations such as T60M and D486N are more commonly observed 14 , 15 . The p.C421F mutation in SLC12A3 , identified in this study as a clustered variant associated with GS, has previously been reported in a Chinese patient (compound heterozygote) and a Japanese patient (homozygote). Our findings confirm that the p.C421F variant represents a founder mutation in this specific population. Located in the southwestern border region of China and adjacent to Myanmar and Vietnam, Yunnan Province is characterized by mountainous terrain that forms natural genetic barriers. Geographically isolated communities or those practicing consanguinity or endogamy may give rise to founder mutations 16 . Through LD analysis, we identified strong LD surrounding the mutation site (Chr16:56913066) (Fig. 2 -A). Haplotype analysis revealed that 17 GS patients shared a common haplotype of at least 499 kb in length (Chr16:56686471–57185949) (Fig. 2 -B), confirming the presence of a founder mutation. The Yi ethnic community in Yunnan maintains unique lifestyle traditions and marital practices, which likely contributed to the emergence and preservation of this founder mutation associated with GS in the region. Moreover, discrepancies in haplotype structure between patients F1-Ⅱ-1 and F12-Ⅱ-2 suggest the possible existence of alternative haplotypes or low-frequency pathogenic variants within this population. Expanding the sample size or applying long-read sequencing may facilitate the identification of additional pathogenic variants 17 , 18 . Founder mutations and founder effects not only shape the geographic distribution of genetic disorders but also offer important insights into genetic diversity and disease susceptibility. Investigating these effects enables the development of population-tailored genetic screening and diagnostic strategies, thereby enhancing the early detection and management of hereditary diseases. It is essential to consider population-specific characteristics of diseases when developing diagnostic tools, particularly for diseases that are phenotypically homogeneous but genetically heterogeneous 17 . In certain scenarios, especially when clinical diagnosis is challenging and biochemical tests are not sufficiently reliable, molecular testing becomes a more suitable and effective approach 19 . Screening for the founder mutation p.C421F in SLC12A3 may serve as the first-line diagnostic step for GS in Yi communities in Yunnan, where the majority of GS patients are homozygous for this variant. Although other pathogenic variants have been reported in GS patients elsewhere in China, testing for this specific mutation should be prioritized in this region. Given the limited healthcare resources, screening for the founder mutation offers an option for molecular diagnosis that is rapid and cost-effective. With targeted gene sequencing and related technologies, high-risk individuals can be screened for the founder mutation to assess the risk of transmitting GS to offspring 20 . In addition, preimplantation genetic testing for monogenic disorders (PGT-M) can be used to effectively identify and prevent the transmission of such conditions 21 . Furthermore, continued monitoring and investigation of founder mutations will not only enhance understanding of the disease but also provide more precise medical care and genetic counseling for affected individuals and their families 22 . Conclusions We investigated and reported a high prevalence of GS in a Yi ethnic community in Yunnan Province and confirmed that this is attributable to a founder effect of the SLC12A3 p.C421F mutation. These findings may support the development of measures to screen carriers and contribute to the implementation of region-specific strategies for the prevention of genetic disorders. Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki, with written informed consent obtained from all patients or their legal guardians. The study protocol was approved by the Ethics Committee of the People's Hospital of Chuxiong Yi Autonomous Prefecture (KYCS2024017). Consent for publication Not applicable. Availability of data and materials All data supporting this study are included in this manuscript. Competing interests The authors declare no competing interests. Funding Yunnan Provincial Department of Education Scientifc Research（2025J0793）；National Clinical Key Specialty Construction Project of Cardiovascular Medicine at Chuxiong People's Hospital（2024ZK01）；Scientific Research Project of Chuxiong Medical College（2019YYMX01）；Scientific Research Fund of the People's Hospital of Chuxiong Yi Autonomous Prefecture（2023Y05） Author's ’contribution Y-G Xie and Heng Luo organized and designed the study. Heng Luo also provided funding support for the project. Jian Han was responsible for implementing the research and drafting the manuscript. Jinghua Gao, Lanxin Ma, and Honghan Zhang contributed to the management of the database and the follow-up of patients. Ying Hu, Wenqian Zhao, Xiaoling Liu, Xiaojun Li, and Jin He assisted with the study design and statistical analysis.All authors reviewed the manuscript. Acknowledgement Not applicable. References Blanchard A et al. Gitelman syndrome: consensus and guidance from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int 2017; 91: 24–33. Calò LA, Marchini F, Davis PA, Rigotti P, Pagnin E, Semplicini A. Kidney transplant in gitelman’s syndrome. Report of the first case. J Nephrol. 2003;16:144–7. Bonfante L, et al. Chronic renal failure, end-stage renal disease, and peritoneal dialysis in gitelman’s syndrome. Am J Kidney Dis Off J Natl Kidney Found. 2001;38:165–8. Kondo A, et al. Examination of the predicted prevalence of gitelman syndrome by ethnicity based on genome databases. Sci Rep. 2021;11:16099. Hsu Y-J, Yang S-S, Chu N-F, Sytwu H-K, Cheng C-J, Lin S-H. Heterozygous mutations of the sodium chloride cotransporter in chinese children: prevalence and association with blood pressure. Nephrol Dial Transpl Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2009;24:1170–5. Tseng M-H, et al. Genotype, phenotype, and follow-up in taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. J Clin Endocrinol Metab. 2012;97:E1478–1482. Wang F, Shi C, Cui Y, Li C, Tong A. Mutation profile and treatment of gitelman syndrome in chinese patients. Clin Exp Nephrol. 2017;21:293–9. Garagiola I, et al. A recurrent F8 mutation (c.6046C > T) causing hemophilia a in 8% of northern italian patients: evidence for a founder effect. Mol Genet Genomic Med. 2016;4:152–9. Fanis P, Efstathiou E, Neocleous V, Phylactou LA, Hadjipanayis A. A novel heterozygous duplication of the SLC12A3 gene in two gitelman syndrome pedigrees: indicating a founder effect. J Genet. 2019;98:5. Richards S, 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 Off J Am Coll Med Genet. 2015;17:405–24. Stern C. The hardy-weinberg law. Science. 1943;97:137–8. Tseng M-H, et al. Genotype, phenotype, and follow-up in taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. J Clin Endocrinol Metab. 2012;97:E1478–1482. Glaudemans B, et al. Novel NCC mutants and functional analysis in a new cohort of patients with gitelman syndrome. Eur J Hum Genet EJHG. 2012;20:263–70. Mou L, Tang M, Zhu L, Lin W, Gu Y. Spectrum of variants in a large chinese gitelman syndrome cohort. Clin Genet. 2023;104:674–8. Fan M, Zhang J, Lee C-L, Zhang J, Feng L. Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter. Nature. 2023;614:788–93. Sheth H, et al. The GALNS p.P77R variant is a probable gujarati-indian founder mutation causing mucopolysaccharidosis IVA syndrome. BMC Genomics. 2022;23:458. Zlotogora J. Knowing the ethnic origin of the patient is important in making a diagnosis. Am J Med Genet. 1998;78:393–4. Rossanti R, et al. Detecting pathogenic deep intronic variants in gitelman syndrome. Am J Med Genet A. 2022;188:2576–83. Civeira F, et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. Am J Cardiol. 2008;102:1187–93. 1193.e1. Punj S, et al. Preconception carrier screening by genome sequencing: results from the clinical laboratory. Am J Hum Genet. 2018;102:1078–89. Wu Z, Liang T, Liu Y, Ding X, Shu D. Using preimplantation genetic testing for monogenic disease for preventing citrullinemia type 1 transmission. Front Genet. 2024;15:1389461. Lambie L, Amin R, Essop F, Cnaan A, Krause A, Guay-Woodford LM. Clinical and genetic characterization of a founder PKHD1 mutation in afrikaners with ARPKD. Pediatr Nephrol Berl Ger. 2015;30:273–9. Supplementary Files Tab1.png Supplementary Table 1. 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16:20:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7109230/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7109230/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87344130,"identity":"50ea409f-761c-4255-9e47-6fc2dd0a9d91","added_by":"auto","created_at":"2025-07-23 01:57:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":154032,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFamily pedigree charts 1 - 12 were presented.\u003c/strong\u003e Sanger sequencing verification was performed on 19 patients with GS. The results showed that all patients were homozygotes for the\u003cem\u003e SLC12A3\u003c/em\u003e (NM_000339.9): c.1262G\u0026gt;T (p.C421F).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7109230/v1/98ebe2d3856a960dc7d89fc1.png"},{"id":87344141,"identity":"ad4a3f01-9d78-4c3d-9bf6-d0092a86b62d","added_by":"auto","created_at":"2025-07-23 01:57:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":192502,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA \u003c/strong\u003eThe p.C421F variant in \u003cem\u003eSLC12A3\u003c/em\u003e was identified in 19 patients with GS. The intensity of red represents the strength of LD (measured by R²) between SNPs. The arrow indicates the mutation site at Chr16:56913066.\u003cstrong\u003eB \u003c/strong\u003eA shared haplotype of at least 499 kb (Chr16:56686471–57185949) was identified in 17 GS patients. Individuals F1-Ⅱ-1and F12-Ⅱ-2 do not share this haplotype.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7109230/v1/fd070b1b6ef92ea7c8df2de8.png"},{"id":88215349,"identity":"7e4fa556-6d73-4911-a54b-a7a0c02d9e75","added_by":"auto","created_at":"2025-08-04 06:42:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":698484,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7109230/v1/7eb61814-278e-40ed-a725-7ca452296f88.pdf"},{"id":87344129,"identity":"2e8907a7-1b7a-4a83-a4cc-75bfaca59d26","added_by":"auto","created_at":"2025-07-23 01:57:50","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33962,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1.\u003c/p\u003e","description":"","filename":"Tab1.png","url":"https://assets-eu.researchsquare.com/files/rs-7109230/v1/d30cb202b7025617ad57e964.png"}],"financialInterests":"","formattedTitle":"Founder Mutation p.C421F in SLC12A3 Underlies the High Prevalence of Gitelman Syndrome in the Yi Population of China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGitelman syndrome (GS, OMIM #263800), also referred to as familial hypokalemia and hypomagnesemia, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. It is caused by biallelic loss-of-function variants in the \u003cem\u003eSLC12A3\u003c/em\u003e gene (OMIM *600968)\u003csup\u003e2,3\u003c/sup\u003e The estimated prevalence of GS is approximately 1\u0026ndash;10 per 40,000 individuals in Europe\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, while in Japan, it may be as high as 10.3 per 10,000 individuals\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. A study involving Chinese children reported a heterozygous \u003cem\u003eSLC12A3\u003c/em\u003e variant frequency of approximately 2.9%\u003csup\u003e5\u003c/sup\u003e. In another cohort of Chinese school-aged children (n\u0026thinsp;=\u0026thinsp;500), the allele frequency of heterozygous \u003cem\u003eSLC12A3\u003c/em\u003e mutations was found to be 3%\u003csup\u003e6\u003c/sup\u003e, suggesting a potentially unique genetic predisposition in the Chinese population. However, comprehensive epidemiological data on the actual prevalence remains lacking\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIt is noteworthy that when a small subgroup separates from a larger population and establishes a new community, certain genetic mutations present in the original population may become more prevalent in the new group due to genetic drift, leading to what is known as the founder effect\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The elevated mutation frequencies in geographically isolated populations often indicate the possible involvement of founder mutations. For instance, the exon 9\u0026ndash;14 duplication (E9_E14dup) identified in individuals of Greek Cypriot descent has been recognized as a founder mutation among GS patients in that region\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. This study reports a clustering of GS cases within a Yi ethnic community in Yunnan, China, based on the identification of two GS patients carrying the \u003cem\u003eSLC12A3\u003c/em\u003e c.1262G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.C421F) mutation through population screening and case tracing. Moreover, haplotype analysis confirmed, for the first time, the presence of a founder mutation in this population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA total of 1,000 volunteers were randomly recruited from a Yi ethnic community in Yunnan, China, to screen for the p.C421F mutation of \u003cem\u003eSLC12A3\u003c/em\u003e (ENST00000438926, NM_000339.3) using Sanger sequencing. The PCR primer sequences were as follows: forward: 5\u0026prime;-GATGCCTCTGGGGTCCTGAA-3\u0026prime;; reverse: 5\u0026prime;-TCGCAAAGGCACTGGAAGAC-3\u0026prime;. PCR amplification was followed by Sanger sequencing on an ABI 3500xL Dx Genetic Analyzer. Based on the sequencing results, pedigree investigations were conducted for individuals identified as heterozygous carriers and for families of patients diagnosed with GS.\u003c/p\u003e\u003cp\u003eWhole-exome sequencing (WES) was performed on all patients diagnosed with GS by Sanger sequencing using the MGISEQ-2000 platform. Following quality control, 204,443 autosomal single nucleotide polymorphisms (SNPs) loci were retained for analysis. The Human GRCh38/hg38 assembly was used as the reference genome, and genotype imputation was conducted with Beagle 5. Haplotype analysis was conducted using PLINK. Preliminary quality control was performed in PLINK (minor allele frequency [MAF]\u0026thinsp;\u0026gt;\u0026thinsp;0.01, missing rate\u0026thinsp;\u0026lt;\u0026thinsp;5%), and haplotype blocks were defined based on linkage disequilibrium (LD) using the --blocks command. The pathogenicity of candidate variants was interpreted according to the guidelines of the American College of Medical Genetics and Genomics (ACMG)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTargeted sequencing for the p.C421F variant identified 55 heterozygous carriers and two individuals with GS among 1,000 participants, spanning 12 distinct families. Based on Hardy-Weinberg equilibrium, the estimated allele frequency of the variant was approximately 3%. Given a total population of approximately 20,000 in this region, the estimated local prevalence of p.C421F-associated GS is 1 in 1,000.\u003c/p\u003e\u003cp\u003ePedigree analysis of these 12 families ultimately identified 19 individuals affected by GS. WES confirmed that all patients were homozygous for the p.C421F mutation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Haplotype analysis was conducted on 19 of the GS patients. LD analysis revealed a strong LD block surrounding the mutation site at Chr16:56913066 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-A). Notably, 89.5% (n\u0026thinsp;=\u0026thinsp;17/19) of the GS patients shared a common haplotype of at least 499 kb in length (Chr16:56686471\u0026ndash;57185949) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B).\u003c/p\u003e\u003cp\u003eAmong the 19 identified GS patients, all (100%, n\u0026thinsp;=\u0026thinsp;19/19) exhibited chronic hypokalemia (\u0026lt;\u0026thinsp;3.5 mmol/L) and hypomagnesemia (\u0026lt;\u0026thinsp;0.7 mmol/L). Fatigue was reported in 94.5% of patients (n\u0026thinsp;=\u0026thinsp;18/19), while 89.5% (n\u0026thinsp;=\u0026thinsp;17/19) had hypocalciuria and abnormal renin levels. Additionally, 10.5% of patients (n\u0026thinsp;=\u0026thinsp;2/19) presented with abnormal fasting blood glucose and aldosterone levels. Additional clinical details are provided in Supplementary Table\u0026nbsp;1.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we identified two probands with homozygous p.C421F mutations in \u003cem\u003eSLC12A3\u003c/em\u003e from a Yi ethnic community in Yunnan, China. Based on these findings, we recruited 1,000 local participants and performed targeted sequencing for the p.C421F variant, estimating its allele frequency to be approximately 3%. Pedigree analyses were then conducted among newly identified GS patients and heterozygous carriers. A total of 19 GS patients were identified across 12 families, all of whom were homozygous for the p.C421F mutation. These results indicate that the prevalence of GS attributable to the founder mutation of p.C421F in this population is approximately 1 in 1,000\u003csup\u003e11\u003c/sup\u003e. Given the potential presence of additional pathogenic variants in the \u003cem\u003eSLC12A3\u003c/em\u003e, we speculate that the actual prevalence of GS in this region may be higher than 1 in 1,000. This suggests that there may be underrecognized genetic factors contributing to the elevated prevalence of GS in East Asian populations. Moreover, a study based on genomic databases estimated the predicted prevalence of GS across various ethnic groups and found that the prevalence in the Japanese population, as well as in certain ethnicities, was higher than previously reported\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. These findings suggest that the prevalence of GS in East Asian populations may have been substantially underestimated.\u003c/p\u003e\u003cp\u003eThe distribution of mutant alleles of the \u003cem\u003eSLC12A3\u003c/em\u003e demonstrates significant population heterogeneity\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. In European populations, the predominant variants are R861C and L859P, whereas in Chinese populations, high-frequency mutations such as T60M and D486N are more commonly observed\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The p.C421F mutation in \u003cem\u003eSLC12A3\u003c/em\u003e, identified in this study as a clustered variant associated with GS, has previously been reported in a Chinese patient (compound heterozygote) and a Japanese patient (homozygote). Our findings confirm that the p.C421F variant represents a founder mutation in this specific population.\u003c/p\u003e\u003cp\u003eLocated in the southwestern border region of China and adjacent to Myanmar and Vietnam, Yunnan Province is characterized by mountainous terrain that forms natural genetic barriers. Geographically isolated communities or those practicing consanguinity or endogamy may give rise to founder mutations\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Through LD analysis, we identified strong LD surrounding the mutation site (Chr16:56913066) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-A). Haplotype analysis revealed that 17 GS patients shared a common haplotype of at least 499 kb in length (Chr16:56686471\u0026ndash;57185949) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B), confirming the presence of a founder mutation. The Yi ethnic community in Yunnan maintains unique lifestyle traditions and marital practices, which likely contributed to the emergence and preservation of this founder mutation associated with GS in the region. Moreover, discrepancies in haplotype structure between patients F1-Ⅱ-1 and F12-Ⅱ-2 suggest the possible existence of alternative haplotypes or low-frequency pathogenic variants within this population. Expanding the sample size or applying long-read sequencing may facilitate the identification of additional pathogenic variants\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFounder mutations and founder effects not only shape the geographic distribution of genetic disorders but also offer important insights into genetic diversity and disease susceptibility. Investigating these effects enables the development of population-tailored genetic screening and diagnostic strategies, thereby enhancing the early detection and management of hereditary diseases. It is essential to consider population-specific characteristics of diseases when developing diagnostic tools, particularly for diseases that are phenotypically homogeneous but genetically heterogeneous\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In certain scenarios, especially when clinical diagnosis is challenging and biochemical tests are not sufficiently reliable, molecular testing becomes a more suitable and effective approach\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Screening for the founder mutation p.C421F in \u003cem\u003eSLC12A3\u003c/em\u003e may serve as the first-line diagnostic step for GS in Yi communities in Yunnan, where the majority of GS patients are homozygous for this variant. Although other pathogenic variants have been reported in GS patients elsewhere in China, testing for this specific mutation should be prioritized in this region. Given the limited healthcare resources, screening for the founder mutation offers an option for molecular diagnosis that is rapid and cost-effective. With targeted gene sequencing and related technologies, high-risk individuals can be screened for the founder mutation to assess the risk of transmitting GS to offspring\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In addition, preimplantation genetic testing for monogenic disorders (PGT-M) can be used to effectively identify and prevent the transmission of such conditions\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Furthermore, continued monitoring and investigation of founder mutations will not only enhance understanding of the disease but also provide more precise medical care and genetic counseling for affected individuals and their families\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe investigated and reported a high prevalence of GS in a Yi ethnic community in Yunnan Province and confirmed that this is attributable to a founder effect of the \u003cem\u003eSLC12A3\u003c/em\u003e p.C421F mutation. These findings may support the development of measures to screen carriers and contribute to the implementation of region-specific strategies for the prevention of genetic disorders.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki, with written informed consent obtained from all patients or their legal guardians. The study protocol was approved by the Ethics Committee of the People\u0026apos;s Hospital of Chuxiong Yi Autonomous Prefecture (KYCS2024017).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting this study are included in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003cbr\u003e\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYunnan Provincial Department of Education Scientifc Research（2025J0793）；National Clinical Key Specialty Construction Project of Cardiovascular Medicine at Chuxiong People\u0026apos;s Hospital（2024ZK01）；Scientific Research Project of Chuxiong Medical College（2019YYMX01）；Scientific Research Fund of the People\u0026apos;s Hospital of Chuxiong Yi Autonomous Prefecture（2023Y05）\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s \u0026rsquo;contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY-G Xie and Heng Luo organized and designed the study. Heng Luo also provided funding support for the project. Jian Han was responsible for implementing the research and drafting the manuscript. Jinghua Gao, Lanxin Ma, and Honghan Zhang contributed to the management of the database and the follow-up of patients. Ying Hu, Wenqian Zhao, Xiaoling Liu, Xiaojun Li, and Jin He assisted with the study design and statistical analysis.All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBlanchard A et al. Gitelman syndrome: consensus and guidance from a kidney disease: improving global outcomes (KDIGO) controversies conference. \u003cem\u003eKidney Int\u003c/em\u003e 2017; 91: 24\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCal\u0026ograve; LA, Marchini F, Davis PA, Rigotti P, Pagnin E, Semplicini A. Kidney transplant in gitelman\u0026rsquo;s syndrome. Report of the first case. J Nephrol. 2003;16:144\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBonfante L, et al. Chronic renal failure, end-stage renal disease, and peritoneal dialysis in gitelman\u0026rsquo;s syndrome. Am J Kidney Dis Off J Natl Kidney Found. 2001;38:165\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKondo A, et al. Examination of the predicted prevalence of gitelman syndrome by ethnicity based on genome databases. Sci Rep. 2021;11:16099.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHsu Y-J, Yang S-S, Chu N-F, Sytwu H-K, Cheng C-J, Lin S-H. Heterozygous mutations of the sodium chloride cotransporter in chinese children: prevalence and association with blood pressure. Nephrol Dial Transpl Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2009;24:1170\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTseng M-H, et al. Genotype, phenotype, and follow-up in taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. J Clin Endocrinol Metab. 2012;97:E1478\u0026ndash;1482.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang F, Shi C, Cui Y, Li C, Tong A. Mutation profile and treatment of gitelman syndrome in chinese patients. Clin Exp Nephrol. 2017;21:293\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGaragiola I, et al. A recurrent F8 mutation (c.6046C\u0026thinsp;\u0026gt;\u0026thinsp;T) causing hemophilia a in 8% of northern italian patients: evidence for a founder effect. Mol Genet Genomic Med. 2016;4:152\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFanis P, Efstathiou E, Neocleous V, Phylactou LA, Hadjipanayis A. A novel heterozygous duplication of the SLC12A3 gene in two gitelman syndrome pedigrees: indicating a founder effect. J Genet. 2019;98:5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRichards S, 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 Off J Am Coll Med Genet. 2015;17:405\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStern C. The hardy-weinberg law. Science. 1943;97:137\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTseng M-H, et al. Genotype, phenotype, and follow-up in taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. J Clin Endocrinol Metab. 2012;97:E1478\u0026ndash;1482.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGlaudemans B, et al. Novel NCC mutants and functional analysis in a new cohort of patients with gitelman syndrome. Eur J Hum Genet EJHG. 2012;20:263\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMou L, Tang M, Zhu L, Lin W, Gu Y. Spectrum of variants in a large chinese gitelman syndrome cohort. Clin Genet. 2023;104:674\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFan M, Zhang J, Lee C-L, Zhang J, Feng L. Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter. Nature. 2023;614:788\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSheth H, et al. The GALNS p.P77R variant is a probable gujarati-indian founder mutation causing mucopolysaccharidosis IVA syndrome. BMC Genomics. 2022;23:458.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZlotogora J. Knowing the ethnic origin of the patient is important in making a diagnosis. Am J Med Genet. 1998;78:393\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRossanti R, et al. Detecting pathogenic deep intronic variants in gitelman syndrome. Am J Med Genet A. 2022;188:2576\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCiveira F, et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. Am J Cardiol. 2008;102:1187\u0026ndash;93. 1193.e1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePunj S, et al. Preconception carrier screening by genome sequencing: results from the clinical laboratory. Am J Hum Genet. 2018;102:1078\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu Z, Liang T, Liu Y, Ding X, Shu D. Using preimplantation genetic testing for monogenic disease for preventing citrullinemia type 1 transmission. Front Genet. 2024;15:1389461.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLambie L, Amin R, Essop F, Cnaan A, Krause A, Guay-Woodford LM. Clinical and genetic characterization of a founder PKHD1 mutation in afrikaners with ARPKD. Pediatr Nephrol Berl Ger. 2015;30:273\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"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},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7109230/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7109230/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eGitelman syndrome (GS) is an autosomal recessive inherited renal tubular disorder, primarily caused by mutations in the \u003cem\u003eSLC12A3\u003c/em\u003e gene. Its prevalence varies significantly among different populations. Previous studies have found that the incidence rate in the Yunnan Yi community of China is notably higher. Factors such as the founder effect contribute to the unique genetic characteristics observed in isolated populations. This study aims to explore the genetic basis for the increased prevalence of GS in the Yi population, focusing on identifying common mutations in the \u003cem\u003eSLC12A3\u003c/em\u003e gene. Preliminary results suggest that the p.C421F variant may be a founder mutation in this population, which could enhance diagnostic strategies and inform public health initiatives.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eAll patients underwent WES, followed by family analysis and verification with Sanger sequencing.Sanger sequencing was used to detect the p.C421F mutation in 1,000 random volunteers from the Yi population. Haplotype analysis was conducted using PLINK software.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe prevalence of GS in this region is approximately 1 in 1,000, with an allele frequency of 3% for the p.C421F mutation. All 19 GS patients were homozygous for the p.C421F mutation, and a common haplotype surrounding the p.C421F allele was identified in 17 of the GS patients, with a length of at least 499 kb.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOur study reports a higher prevalence of GS in the Yunnan Yi community and confirms that this phenomenon is due to the founder effect of the \u003cem\u003eSLC12A3\u003c/em\u003e gene p.C421F mutation.\u003c/p\u003e","manuscriptTitle":"Founder Mutation p.C421F in SLC12A3 Underlies the High Prevalence of Gitelman Syndrome in the Yi Population of China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 01:57:46","doi":"10.21203/rs.3.rs-7109230/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":"caf6f4c4-4ec9-4b08-a967-cc10339349f3","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-04T06:34:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-23 01:57:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7109230","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7109230","identity":"rs-7109230","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}