A Case of UMOD-Associated Nephropathy Mimicking Focal Segmental Glomerulosclerosis in a Young Male with a Positive Family History

A Case of UMOD-Associated Nephropathy Mimicking Focal Segmental Glomerulosclerosis in a Young Male with a Positive Family History | 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 Case Report A Case of UMOD-Associated Nephropathy Mimicking Focal Segmental Glomerulosclerosis in a Young Male with a Positive Family History Xin He, Jiang Pu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7969434/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2026 Read the published version in BMC Nephrology → Version 1 posted 13 You are reading this latest preprint version Abstract Focal segmental glomerulosclerosis (FSGS) is a pathological manifestation with diverse causes, but its link to UMOD gene mutations - typically associated with autosomal dominant tubulointerstitial kidney disease (ADTKD) - is rare and not well characterized. We report a young male patient with familial nephropathy in whom renal biopsy showed FSGS and whole-exome sequencing identified compound heterozygous pathogenic variants in UMOD (OMIM: 191845), c.113A > T (p.Asn38Ile). This case indicates that UMOD mutations can present primarily as FSGS on biopsy, and the accumulation of mutant uromodulin may initiate tubular injury and ultimately secondary glomerulosclerosis. These findings highlight the necessity of incorporating genetic testing into FSGS evaluation to achieve precise diagnosis and guide management. Focal Segmental Glomerulosclerosis UMOD Gene Mutations Whole exome sequencing case report Figures Figure 1 Figure 2 1. Introduction Focal segmental glomerulosclerosis (FSGS) is a podocyte disease characterized by segmental sclerosis of the glomeruli[ 1 ]. Accounting for approximately 40% of glomerular kidney disease cases in adults[ 2 ], FSGS is a leading cause of kidney failure globally[ 3 ]. The current view is that FSGS is not as a single disease entity, but rather the final common pathway for a heterogeneous group of disorders with diverse etiologies[ 4 ]. To reflect this pathophysiological complexity, the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines adopted a mechanistic classification system that categorizes FSGS into primary (immune-mediated), genetic, secondary/adaptive, and undetermined forms [ 5 ]. In particular, the genetic category has rapidly expanded, with mutations in over 60 genes identified to date, revealing unexpected genotypes and broadening the phenotypic spectrum of hereditary FSGS. UMOD is the most abundant protein in normal urine, formerly known as Tamm-Horsfall glycoprotein, which encodes uromodulin[ 6 ]. More than 100 pathogenic mutations in UMOD have been reported[ 7 ], typically causing Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD)[ 8 ]. The classic presentation of ADTKD-UMOD includes an autosomal dominant inheritance pattern, bland urine sediment with minimal proteinuria, hyperuricemia, early-onset gout, and a slow progression to end-stage renal disease typically between the third and seventh decades of life[ 6 , 9 , 10 ]. Its insidious onset and often subtle urinary findings requires a high index of clinical suspicion for the diagnosis of ADTKD-UMOD, and is ultimately confirmed by genetic testing. Notably, emerging evidence challenges the traditional view of UMOD-associated disease as a purely tubulointerstitial disorder. Recent studies have identified UMOD variants in patients with a histopathological diagnosis of FSGS, a finding that was initially unexpected given the protein's primary tubular origin[ 1 ].This suggests that the clinicopathological presentation of UMOD-related nephropathy may be more widespread than previously recognized, and some patients clinically diagnosed with FSGS may have potential UMOD mutations. In this case, a patient with a renal biopsy confirming FSGS was found through whole-exome sequencing to carry a compound heterozygous mutation in the UMOD gene, emphasizing the diagnostic complexity and expanded the genotypic spectrum of UMOD-related disease. This case highlights the critical role of comprehensive genetic testing in the evaluation of FSGS and contributes to the evolving understanding of the phenotypic manifestations of UMOD mutations. 2. Case presentation 2.1 Patients and clinical evaluation A 33-year-old man was admitted to our Department because of abnormal renal function, with a significant family history of kidney disease affecting his mother, sister, aunt, and cousin (Fig. 1 ). Four years ago, he experienced an increase in blood creatinine, but no followed-up diagnosis or treatment was conducted. Ten days ago, for further diagnosis and treatment, he was admitted to our Department. Physical examination showed no obvious abnormality. Laboratory investigations confirmed a serum creatinine level of 128µmol/L and a 24-hour urinary protein excretion of 0.25g. Serum chemistry showed elevated levels of serum creatinine, uric acid, parathyroid hormone (Table 1 ). Immunological profiles were within normal limits. Abdominal ultrasound examination showed normal-sized of kidney but with hyperechogenicity; the remainder of the examination was unremarkable. Renal ECT indicates mild impairment of bilateral renal filtration function. Table 1 Abnormal laboratory data at admission. Parameters Patient Reference range Urine routine tests Urine protein 1+ Negative Urinary occult blood 2+ Negative 24-hour UP, g/d 0.25 0-0.15 Serum chemistry Creatinine, umol/L 128 57–111 Uric acid, umol/L 464.1 208–428 PTH, pg/ml 66.3 15–65 After exclusion of contraindications, a biopsy of the kidney was performed. Immunostaining for IgA, IgG, IgM(Fig. 2A1), C3, C4, C1q, ALB (Fig. 2A2), κ, λ, etc. was negative. Electron microscopy revealed a glomerular basement membrane of normal thickness and segmental foot process effacement, ranging from partial to extensive. A small number of low-density electron-dense deposits were noted in occasional mesangial areas (Fig. 2 B). Histochemistry identified advanced chronic kidney pathology, with 10 of 12 glomeruli sclerotic. The injury pattern included glomerular sclerosis ranging from global to segmental (Fig. 2 C), mild mesangial hyperplasia (Fig. 2 D), and an absence of basement membrane remodeling (Fig. 2 E). The process was further defined by concomitant tubulointerstitial injury (vacuolization, inflammation, fibrosis) and arteriosclerosis (Fig. 2 F). C-F. Histological staining diagram: C. glomerulosclerosis (structural collapse and sclerosis); Vacuolar degeneration of renal tubular epithelial cells; Renal interstitial fibrosis with inflammatory cell infiltration; Arteriolar wall thickening and luminal narrowing (HE×100). D. Mesangium : Mild proliferation of cells and matrix with resultant architectural widening. Capillary Loops : Patent; no significant basement membrane thickening, spike formation, mesangial interposition, or double tracks. Bowman's Capsule : No obvious parietal layer thickening or cellular proliferation (PAS×400). E. Periglomerular fibrosis and segmental sclerosis; Mild mesangial hypercellularity and matrix expansion; No significant basement membrane thickening, spike formation, or double tracks (PASM×400). F. Renal interstitium: Focal fibrosis (blue-stained areas); Arterioles: Wall thickening and luminal narrowing (blue-stained wall hyperplasia) (Masson×400). A1-2. immunofluorescence diagram: no obvious deposition of IgM (A1) and ALB (A2) of immune complexes. B1-3. Electron microscopy: Glomeruli : Capillary endothelial cells showed marked vacuolar degeneration. Visceral epithelial cells (podocytes) were swollen and vacuolated, with segmental foot process effacement that was extensive in areas (B3). Mesangium : Mesangial hypercellularity and matrix expansion were noted, with scattered, low-density electron-dense deposits observed locally. Tubules : Vacuolar degeneration was present in the renal tubular epithelial cells. Figure 2 . Histopathology study of renal biopsy from the proband. The findings from light microscopy, immunofluorescence, and electron microscopy collectively support a diagnosis of FSGS, with the majority of glomeruli showing sclerosis. Given the patient's familial nephropathy, genetic testing is recommended to evaluate for possible secondary causes of FSGS. 2.2. Genetic analysis Following whole-exome sequencing identified a heterozygous missense variant in UMOD (OMIM: 191845), c.113A > T (p.Asn38Ile). Genetic testing was conducted commercially/by an external diagnostic lab (Medical Genetics Center, Sichuan Provincial People's Hospital) using whole-exome sequencing. Variant annotation and pathogenicity assessment were performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The full clinical report is available as supplementary material. The UMOD variant was submitted to the ClinVar database (SUB15747924). This variant, located in the highly conserved exon 3 of UMOD, is classified as a "Variant of Uncertain Significance" per ACMG guidelines. This designation is primarily supported by the PM2 criterion (absent from population databases). Notably, the identical c.113A > T change has been previously reported in cases of autosomal dominant tubulointerstitial kidney disease (ADTKD). Table.2 Whole exome sequencing test results. Gene Genomic Coordinate (GRCh38) Transcript & Exon Nucleotide & Amino Acid Change Zygosity Population Frequency Pathogenicity Prediction ACMG Classification Inheritance Pattern Associated Disease Variant Origin UMOD chr16: 20360510 NM_003361.4: exon 3 c.113A > T (p.Asn38Ile) Het - - VUS AD ADTKD unknown Abbreviations:ACMG: American College of Medical Genetics and Genomics; VUS: Variant of Uncertain Significance; Het: Heterozygous; AD: Autosomal Dominant; -: Not detected/Not available. ADTKD: Autosomal Dominant Tubulointerstitial Kidney Disease. Given the suspected genetic mechanism, corticosteroids and immunosuppressants (e.g. CNI) were deemed ineffective. The patient's management was therefore limited to ACEI/ARB therapy, supportive care, active management of hyperuricemia, and genetic counseling. 3. Discussion This article reports a case of UMOD-associated nephropathy mimicking FSGS in a male with a family history of kidney disease, which has the following enlightenments: The patient had a 4-year history of renal disease that was notable for minimal proteinuria and stable renal function. However, the renal biopsy demonstrated severe glomerular injury. This striking discordance between clinical manifestations and pathological severity affirms the essential role of biopsy in diagnosis. Besides, this patient had a clear family history and biopsy findings of FSGS; however, genetic testing identified a heterozygous UMOD mutation (c.113A > T; p.Asn38Ile)—a gene typically associated with tubulointerstitial disease. This case challenges the conventional pathological classification, but some investigations have observed similar phenomena. For example, Bleyer et al[ 11 ] noted in early family studies that in familial adolescent hyperuricemic nephropathy (FJHN) patients carrying UMOD gene mutations, in addition to typical tubulointerstitial lesions, some members also exhibited focal glomerulosclerosis and global sclerosis in renal pathology. Chun et al[ 1 ] investigated eight affected members of families initially believed to have FSGS, but ultimately diagnosed with ADTKD-UMOD. It indicates that UMOD gene may not only be associated with tubulointerstitial disease, but also cause segmental glomerular sclerosis through immune mediation[ 12 ], which is consistent with Trudu et al[ 13 ]. Nafar et al[ 14 ] further suggested that uromodulin might be a biomarker of FSGS. Because the renal pathology in ADTKD-UMOD is typically nonspecific on conventional biopsy, some affected individuals may be misdiagnosed with FSGS[ 14 ]. Thus, when ADTKD-UMOD is clinically suspected, uromodulin immunostaining should be performed. If a UMOD variant is subsequently found in a patient diagnosed with FSGS, reclassification as ADTKD-UMOD is appropriate[ 1 ]. For this patient's condition, a standard treatment has not been established per current guidelines. Therapies like glucocorticoids and CNIs are considered ineffective and are therefore typically avoided[ 15 ]. Due to the patient's immediate fertility needs, management was limited to supportive care. This allowed the avoidance of glucocorticoid and immunosuppressant-related side effects. This study has a key limitation: we were unable to perform genetic testing on the patient's affected family members. This precluded confirmation of co-segregation of the UMOD variant with the disease phenotype and verification of a shared genetic etiology among all affected relatives. In summary, this case supports that UMOD mutations can underlie an FSGS histologic phenotype. Early genetic testing in patients with FSGS and a family history is essential to prevent unnecessary immunosuppression and enable personalized treatment. Declarations Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We wish to thank the patient for participation in the study. Statement of Ethics All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration. Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contributions XH: conception and design. XH and JP: development of methodology and acquisition of data. writing and review the manuscript. All authors: contributed to the article and approved the submitted version. Data Availability Statement The dataset supporting the conclusions of this article is available in the ClinVar repository, under accession number SUB15747924. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images and genetic data. References Chun J, Wang M, Wilkins MS, Knob AU, Benjamin A, Bu L, Pollak MR: Autosomal Dominant Tubulointerstitial Kidney Disease—Uromodulin Misclassified as Focal Segmental Glomerulosclerosis or Hereditary Glomerular Disease . Kidney International Reports 2020, 5 (4):519-529. McGrogan A, Franssen CFM, de Vries CS: The incidence of primary glomerulonephritis worldwide: a systematic review of the literature . Nephrology Dialysis Transplantation 2010, 26 (2):414-430. Rosenberg AZ, Kopp JB: Focal Segmental Glomerulosclerosis . Clinical journal of the American Society of Nephrology : CJASN 2017, 12 (3):502-517. Mitrotti A, Giliberti M, Di Leo V, di Bari I, Pontrelli P, Gesualdo L: Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis? Pediatric Nephrology 2023, 39 (6):1685-1707. Kidney Disease: Improving Global Outcomes Glomerular Diseases Work G: KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases . Kidney international 2021, 100 (4S):S1-S276. Devuyst O, Olinger E, Rampoldi L: Uromodulin: from physiology to rare and complex kidney disorders . Nature Reviews Nephrology 2017, 13 (9):525-544. Qiao P, Wang Z, Xie J: Autosomal dominant tubulointerstitial kidney disease-UMOD: a short review . Orphanet J Rare Dis 2025, 20 (1):405. Olinger E, Hofmann P, Kidd K: Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1 . Kidney international 2020, 98 (3):717-731. Yamazaki H, Nozu K, Narita I, Nagata M: Atypical phenotype of type I Bartter syndrome accompanied by focal segmental glomerulosclerosis . Pediatric nephrology (Berlin, Germany) 2009, 24 (2):415-418. Bollée G, Karin Dahan, Martin Flamant, Vincent Morinière, Audrey Pawtowski: Phenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations . Clinical journal of the American Society of Nephrology : CJASN 2011, 6 (10):2429-2438. Bleyer AJ, Hart PS, Kmoch S: Hereditary Interstitial Kidney Disease . Seminars in nephrology 2010, 30 (4):366-373. Bellur SS, Troyanov S, Vorobyeva O: Evidence from the large VALIGA cohort validates the subclassification of focal segmental glomerulosclerosis in IgA nephropathy . Kidney international 2024, 105 (6):1279-1290. Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G et al : Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression . Nature Medicine 2013, 19 (12):1655-1660. Nafar M, Kalantari S, Samavat S, Rezaei-Tavirani M, Rutishuser D, Zubarev RA: The Novel Diagnostic Biomarkers for Focal Segmental Glomerulosclerosis . International Journal of Nephrology 2014, 2014 :1-10. Tato AM, Carrera N, García-Murias M, Shabaka A, Ávila A, Mora Mora MT, Rabasco C, Soto K, de la Prada Alvarez FJ, Fernández-Lorente L et al : Genetic testing in focal segmental glomerulosclerosis: in whom and when? Clin Kidney J 2023, 16 (11):2011-2022. Additional Declarations No competing interests reported. Supplementary Files ClinicalGeneticTestingReport.docx AdditionalFile1CAREChecklist.pdf Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2026 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 05 Jan, 2026 Reviews received at journal 29 Dec, 2025 Reviewers agreed at journal 29 Dec, 2025 Reviews received at journal 18 Nov, 2025 Reviews received at journal 13 Nov, 2025 Reviewers agreed at journal 09 Nov, 2025 Reviewers agreed at journal 06 Nov, 2025 Reviewers agreed at journal 06 Nov, 2025 Reviewers invited by journal 06 Nov, 2025 Editor assigned by journal 06 Nov, 2025 Editor invited by journal 05 Nov, 2025 Submission checks completed at journal 04 Nov, 2025 First submitted to journal 04 Nov, 2025 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. 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1","display":"","copyAsset":false,"role":"figure","size":65073,"visible":true,"origin":"","legend":"\u003cp\u003eFamily Genealogy of Renal Disease Status. APKD, adult polycystic kidney; HD, hemodialysis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7969434/v1/8d80a8511cd0fc576356f3bf.png"},{"id":96200841,"identity":"a9d759ac-2b22-41d8-baa8-1f917408e17d","added_by":"auto","created_at":"2025-11-18 16:28:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1487292,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathology study of renal biopsy from the proband.\u003c/p\u003e\n\u003cp\u003eA1-2. immunofluorescence diagram: no obvious deposition of IgM (A1) and ALB (A2) of immune complexes. B1-3. Electron microscopy: \u003cstrong\u003eGlomeruli\u003c/strong\u003e: Capillary endothelial cells showed marked vacuolar degeneration. Visceral epithelial cells (podocytes) were swollen and vacuolated, with segmental foot process effacement that was extensive in areas (B3).\u003cstrong\u003e Mesangium\u003c/strong\u003e: Mesangial hypercellularity and matrix expansion were noted, with scattered, low-density electron-dense deposits observed locally. \u003cstrong\u003eTubules\u003c/strong\u003e: Vacuolar degeneration was present in the renal tubular epithelial cells.\u003c/p\u003e\n\u003cp\u003eC-F. Histological staining diagram: C. glomerulosclerosis (structural collapse and sclerosis); Vacuolar degeneration of renal tubular epithelial cells; Renal interstitial fibrosis with inflammatory cell infiltration; Arteriolar wall thickening and luminal narrowing (HE×100). D. \u003cstrong\u003eMesangium\u003c/strong\u003e: Mild proliferation of cells and matrix with resultant architectural widening. \u003cstrong\u003eCapillary Loops\u003c/strong\u003e: Patent; no significant basement membrane thickening, spike formation, mesangial interposition, or double tracks. \u003cstrong\u003eBowman's Capsule\u003c/strong\u003e: No obvious parietal layer thickening or cellular proliferation (PAS×400). E. Periglomerular fibrosis and segmental sclerosis; Mild mesangial hypercellularity and matrix expansion; No significant basement membrane thickening, spike formation, or double tracks (PASM×400). F. Renal interstitium: Focal fibrosis (blue-stained areas); Arterioles: Wall thickening and luminal narrowing (blue-stained wall hyperplasia) (Masson×400).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7969434/v1/bd80131bdeac31d14b55cca0.png"},{"id":105755581,"identity":"5fd594a6-28c6-4a25-982a-abfde0deb647","added_by":"auto","created_at":"2026-03-30 16:28:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2901159,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7969434/v1/2a552f14-adfc-4e32-a476-f78776f2ffaa.pdf"},{"id":96200840,"identity":"d884d3b9-5e9c-4ae1-9351-b7778faac132","added_by":"auto","created_at":"2025-11-18 16:28:12","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28012,"visible":true,"origin":"","legend":"","description":"","filename":"ClinicalGeneticTestingReport.docx","url":"https://assets-eu.researchsquare.com/files/rs-7969434/v1/f91153d79e7f448cfade1516.docx"},{"id":96200844,"identity":"732ee110-78b8-4ba0-80a5-19a182d887fd","added_by":"auto","created_at":"2025-11-18 16:28:12","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":140580,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile1CAREChecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7969434/v1/577c85a61c779985ddd8925e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Case of UMOD-Associated Nephropathy Mimicking Focal Segmental Glomerulosclerosis in a Young Male with a Positive Family History","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eFocal segmental glomerulosclerosis (FSGS) is a podocyte disease characterized by segmental sclerosis of the glomeruli[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Accounting for approximately 40% of glomerular kidney disease cases in adults[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], FSGS is a leading cause of kidney failure globally[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The current view is that FSGS is not as a single disease entity, but rather the final common pathway for a heterogeneous group of disorders with diverse etiologies[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To reflect this pathophysiological complexity, the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines adopted a mechanistic classification system that categorizes FSGS into primary (immune-mediated), genetic, secondary/adaptive, and undetermined forms [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In particular, the genetic category has rapidly expanded, with mutations in over 60 genes identified to date, revealing unexpected genotypes and broadening the phenotypic spectrum of hereditary FSGS.\u003c/p\u003e\u003cp\u003eUMOD is the most abundant protein in normal urine, formerly known as Tamm-Horsfall glycoprotein, which encodes uromodulin[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. More than 100 pathogenic mutations in UMOD have been reported[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], typically causing Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The classic presentation of ADTKD-UMOD includes an autosomal dominant inheritance pattern, bland urine sediment with minimal proteinuria, hyperuricemia, early-onset gout, and a slow progression to end-stage renal disease typically between the third and seventh decades of life[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Its insidious onset and often subtle urinary findings requires a high index of clinical suspicion for the diagnosis of ADTKD-UMOD, and is ultimately confirmed by genetic testing.\u003c/p\u003e\u003cp\u003eNotably, emerging evidence challenges the traditional view of UMOD-associated disease as a purely tubulointerstitial disorder. Recent studies have identified UMOD variants in patients with a histopathological diagnosis of FSGS, a finding that was initially unexpected given the protein's primary tubular origin[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].This suggests that the clinicopathological presentation of UMOD-related nephropathy may be more widespread than previously recognized, and some patients clinically diagnosed with FSGS may have potential UMOD mutations.\u003c/p\u003e\u003cp\u003eIn this case, a patient with a renal biopsy confirming FSGS was found through whole-exome sequencing to carry a compound heterozygous mutation in the UMOD gene, emphasizing the diagnostic complexity and expanded the genotypic spectrum of UMOD-related disease. This case highlights the critical role of comprehensive genetic testing in the evaluation of FSGS and contributes to the evolving understanding of the phenotypic manifestations of UMOD mutations.\u003c/p\u003e"},{"header":"2. Case presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Patients and clinical evaluation\u003c/h2\u003e\u003cp\u003eA 33-year-old man was admitted to our Department because of abnormal renal function, with a significant family history of kidney disease affecting his mother, sister, aunt, and cousin (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Four years ago, he experienced an increase in blood creatinine, but no followed-up diagnosis or treatment was conducted.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTen days ago, for further diagnosis and treatment, he was admitted to our Department. Physical examination showed no obvious abnormality. Laboratory investigations confirmed a serum creatinine level of 128\u0026micro;mol/L and a 24-hour urinary protein excretion of 0.25g. Serum chemistry showed elevated levels of serum creatinine, uric acid, parathyroid hormone (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Immunological profiles were within normal limits. Abdominal ultrasound examination showed normal-sized of kidney but with hyperechogenicity; the remainder of the examination was unremarkable. Renal ECT indicates mild impairment of bilateral renal filtration function.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAbnormal laboratory data at admission.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference range\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine routine tests\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine protein\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary occult blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24-hour UP, g/d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0-0.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum chemistry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine, umol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e128\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57\u0026ndash;111\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUric acid, umol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e464.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e208\u0026ndash;428\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePTH, pg/ml\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u0026ndash;65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAfter exclusion of contraindications, a biopsy of the kidney was performed. Immunostaining for IgA, IgG, IgM(Fig.\u0026nbsp;2A1), C3, C4, C1q, ALB (Fig.\u0026nbsp;2A2), κ, λ, etc. was negative. Electron microscopy revealed a glomerular basement membrane of normal thickness and segmental foot process effacement, ranging from partial to extensive. A small number of low-density electron-dense deposits were noted in occasional mesangial areas (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Histochemistry identified advanced chronic kidney pathology, with 10 of 12 glomeruli sclerotic. The injury pattern included glomerular sclerosis ranging from global to segmental (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), mild mesangial hyperplasia (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eD), and an absence of basement membrane remodeling (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). The process was further defined by concomitant tubulointerstitial injury (vacuolization, inflammation, fibrosis) and arteriosclerosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eF).\u003c/p\u003e\u003cp\u003eC-F. Histological staining diagram: C. glomerulosclerosis (structural collapse and sclerosis); Vacuolar degeneration of renal tubular epithelial cells; Renal interstitial fibrosis with inflammatory cell infiltration; Arteriolar wall thickening and luminal narrowing (HE\u0026times;100). D. \u003cb\u003eMesangium\u003c/b\u003e: Mild proliferation of cells and matrix with resultant architectural widening. \u003cb\u003eCapillary Loops\u003c/b\u003e: Patent; no significant basement membrane thickening, spike formation, mesangial interposition, or double tracks. \u003cb\u003eBowman's Capsule\u003c/b\u003e: No obvious parietal layer thickening or cellular proliferation (PAS\u0026times;400). E. Periglomerular fibrosis and segmental sclerosis; Mild mesangial hypercellularity and matrix expansion; No significant basement membrane thickening, spike formation, or double tracks (PASM\u0026times;400). F. Renal interstitium: Focal fibrosis (blue-stained areas); Arterioles: Wall thickening and luminal narrowing (blue-stained wall hyperplasia) (Masson\u0026times;400).\u003c/p\u003e\u003cp\u003eA1-2. immunofluorescence diagram: no obvious deposition of IgM (A1) and ALB (A2) of immune complexes. B1-3. Electron microscopy: \u003cb\u003eGlomeruli\u003c/b\u003e: Capillary endothelial cells showed marked vacuolar degeneration. Visceral epithelial cells (podocytes) were swollen and vacuolated, with segmental foot process effacement that was extensive in areas (B3). \u003cb\u003eMesangium\u003c/b\u003e: Mesangial hypercellularity and matrix expansion were noted, with scattered, low-density electron-dense deposits observed locally. \u003cb\u003eTubules\u003c/b\u003e: Vacuolar degeneration was present in the renal tubular epithelial cells.\u003c/p\u003e\u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Histopathology study of renal biopsy from the proband.\u003c/p\u003e\u003cp\u003eThe findings from light microscopy, immunofluorescence, and electron microscopy collectively support a diagnosis of FSGS, with the majority of glomeruli showing sclerosis. Given the patient's familial nephropathy, genetic testing is recommended to evaluate for possible secondary causes of FSGS.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Genetic analysis\u003c/h2\u003e\u003cp\u003eFollowing whole-exome sequencing identified a heterozygous missense variant in UMOD (OMIM: 191845), c.113A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Asn38Ile). Genetic testing was conducted commercially/by an external diagnostic lab (Medical Genetics Center, Sichuan Provincial People's Hospital) using whole-exome sequencing. Variant annotation and pathogenicity assessment were performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The full clinical report is available as supplementary material. The UMOD variant was submitted to the ClinVar database (SUB15747924).\u003c/p\u003e\u003cp\u003eThis variant, located in the highly conserved exon 3 of UMOD, is classified as a \"Variant of Uncertain Significance\" per ACMG guidelines. This designation is primarily supported by the PM2 criterion (absent from population databases). Notably, the identical c.113A\u0026thinsp;\u0026gt;\u0026thinsp;T change has been previously reported in cases of autosomal dominant tubulointerstitial kidney disease (ADTKD).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"11\" nameend=\"c11\" namest=\"c1\"\u003e\u003cp\u003eTable.2 Whole exome sequencing test results.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGene\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGenomic Coordinate (GRCh38)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTranscript \u0026amp; Exon\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNucleotide \u0026amp; Amino Acid Change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eZygosity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePopulation Frequency\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePathogenicity Prediction\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eACMG Classification\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eInheritance Pattern\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eAssociated Disease\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVariant Origin\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUMOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr16:\u003c/p\u003e\u003cp\u003e20360510\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNM_003361.4: exon 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ec.113A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Asn38Ile)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eADTKD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eunknown\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"11\" nameend=\"c11\" namest=\"c1\"\u003e\u003cp\u003eAbbreviations:ACMG: American College of Medical Genetics and Genomics; VUS: Variant of Uncertain Significance; Het: Heterozygous; AD: Autosomal Dominant; -: Not detected/Not available. ADTKD: Autosomal Dominant Tubulointerstitial Kidney Disease.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eGiven the suspected genetic mechanism, corticosteroids and immunosuppressants (e.g. CNI) were deemed ineffective. The patient's management was therefore limited to ACEI/ARB therapy, supportive care, active management of hyperuricemia, and genetic counseling.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThis article reports a case of UMOD-associated nephropathy mimicking FSGS in a male with a family history of kidney disease, which has the following enlightenments:\u003c/p\u003e\u003cp\u003eThe patient had a 4-year history of renal disease that was notable for minimal proteinuria and stable renal function. However, the renal biopsy demonstrated severe glomerular injury. This striking discordance between clinical manifestations and pathological severity affirms the essential role of biopsy in diagnosis.\u003c/p\u003e\u003cp\u003eBesides, this patient had a clear family history and biopsy findings of FSGS; however, genetic testing identified a heterozygous UMOD mutation (c.113A\u0026thinsp;\u0026gt;\u0026thinsp;T; p.Asn38Ile)\u0026mdash;a gene typically associated with tubulointerstitial disease. This case challenges the conventional pathological classification, but some investigations have observed similar phenomena. For example, Bleyer et al[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] noted in early family studies that in familial adolescent hyperuricemic nephropathy (FJHN) patients carrying UMOD gene mutations, in addition to typical tubulointerstitial lesions, some members also exhibited focal glomerulosclerosis and global sclerosis in renal pathology. Chun et al[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] investigated eight affected members of families initially believed to have FSGS, but ultimately diagnosed with ADTKD-UMOD. It indicates that UMOD gene may not only be associated with tubulointerstitial disease, but also cause segmental glomerular sclerosis through immune mediation[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which is consistent with Trudu et al[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Nafar et al[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] further suggested that uromodulin might be a biomarker of FSGS. Because the renal pathology in ADTKD-UMOD is typically nonspecific on conventional biopsy, some affected individuals may be misdiagnosed with FSGS[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, when ADTKD-UMOD is clinically suspected, uromodulin immunostaining should be performed. If a UMOD variant is subsequently found in a patient diagnosed with FSGS, reclassification as ADTKD-UMOD is appropriate[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFor this patient's condition, a standard treatment has not been established per current guidelines. Therapies like glucocorticoids and CNIs are considered ineffective and are therefore typically avoided[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Due to the patient's immediate fertility needs, management was limited to supportive care. This allowed the avoidance of glucocorticoid and immunosuppressant-related side effects.\u003c/p\u003e\u003cp\u003eThis study has a key limitation: we were unable to perform genetic testing on the patient's affected family members. This precluded confirmation of co-segregation of the UMOD variant with the disease phenotype and verification of a shared genetic etiology among all affected relatives.\u003c/p\u003e\u003cp\u003eIn summary, this case supports that UMOD mutations can underlie an FSGS histologic phenotype. Early genetic testing in patients with FSGS and a family history is essential to prevent unnecessary immunosuppression and enable personalized treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to thank the patient for participation in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXH: conception and design. XH and JP: development of methodology and acquisition of data. writing and review the manuscript. All authors: contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this article is available in the ClinVar repository, under accession number SUB15747924.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images and genetic data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChun J, Wang M, Wilkins MS, Knob AU, Benjamin A, Bu L, Pollak MR: \u003cstrong\u003eAutosomal Dominant Tubulointerstitial Kidney Disease\u0026mdash;Uromodulin Misclassified as Focal Segmental Glomerulosclerosis or Hereditary Glomerular Disease\u003c/strong\u003e. \u003cem\u003eKidney International Reports \u003c/em\u003e2020, 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\u003cstrong\u003eClinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1\u003c/strong\u003e. \u003cem\u003eKidney international \u003c/em\u003e2020, \u003cstrong\u003e98\u003c/strong\u003e(3):717-731.\u003c/li\u003e\n\u003cli\u003eYamazaki H, Nozu K, Narita I, Nagata M: \u003cstrong\u003eAtypical phenotype of type I Bartter syndrome accompanied by focal segmental glomerulosclerosis\u003c/strong\u003e. \u003cem\u003ePediatric nephrology (Berlin, Germany) \u003c/em\u003e2009, \u003cstrong\u003e24\u003c/strong\u003e(2):415-418.\u003c/li\u003e\n\u003cli\u003eBoll\u0026eacute;e G, Karin Dahan, Martin Flamant, Vincent Morini\u0026egrave;re, Audrey Pawtowski: \u003cstrong\u003ePhenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations\u003c/strong\u003e. \u003cem\u003eClinical journal of the American Society of Nephrology : CJASN \u003c/em\u003e2011, \u003cstrong\u003e6\u003c/strong\u003e(10):2429-2438.\u003c/li\u003e\n\u003cli\u003eBleyer AJ, Hart PS, Kmoch S: \u003cstrong\u003eHereditary Interstitial Kidney Disease\u003c/strong\u003e. \u003cem\u003eSeminars in nephrology \u003c/em\u003e2010, \u003cstrong\u003e30\u003c/strong\u003e(4):366-373.\u003c/li\u003e\n\u003cli\u003eBellur SS, Troyanov S, Vorobyeva O: \u003cstrong\u003eEvidence from the large VALIGA cohort validates the subclassification of focal segmental glomerulosclerosis in IgA nephropathy\u003c/strong\u003e. \u003cem\u003eKidney international \u003c/em\u003e2024, \u003cstrong\u003e105\u003c/strong\u003e(6):1279-1290.\u003c/li\u003e\n\u003cli\u003eTrudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCommon noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression\u003c/strong\u003e. \u003cem\u003eNature Medicine \u003c/em\u003e2013, \u003cstrong\u003e19\u003c/strong\u003e(12):1655-1660.\u003c/li\u003e\n\u003cli\u003eNafar M, Kalantari S, Samavat S, Rezaei-Tavirani M, Rutishuser D, Zubarev RA: \u003cstrong\u003eThe Novel Diagnostic Biomarkers for Focal Segmental Glomerulosclerosis\u003c/strong\u003e. \u003cem\u003eInternational Journal of Nephrology \u003c/em\u003e2014, \u003cstrong\u003e2014\u003c/strong\u003e:1-10.\u003c/li\u003e\n\u003cli\u003eTato AM, Carrera N, Garc\u0026iacute;a-Murias M, Shabaka A, \u0026Aacute;vila A, Mora Mora MT, Rabasco C, Soto K, de la Prada Alvarez FJ, Fern\u0026aacute;ndez-Lorente L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenetic testing in focal segmental glomerulosclerosis: in whom and when?\u003c/strong\u003e \u003cem\u003eClin Kidney J \u003c/em\u003e2023, \u003cstrong\u003e16\u003c/strong\u003e(11):2011-2022.\u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Focal Segmental Glomerulosclerosis, UMOD, Gene Mutations, Whole exome sequencing, case report","lastPublishedDoi":"10.21203/rs.3.rs-7969434/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7969434/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eFocal segmental glomerulosclerosis (FSGS) is a pathological manifestation with diverse causes, but its link to UMOD gene mutations - typically associated with autosomal dominant tubulointerstitial kidney disease (ADTKD) - is rare and not well characterized. We report a young male patient with familial nephropathy in whom renal biopsy showed FSGS and whole-exome sequencing identified compound heterozygous pathogenic variants in UMOD (OMIM: 191845), c.113A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Asn38Ile). This case indicates that UMOD mutations can present primarily as FSGS on biopsy, and the accumulation of mutant uromodulin may initiate tubular injury and ultimately secondary glomerulosclerosis. These findings highlight the necessity of incorporating genetic testing into FSGS evaluation to achieve precise diagnosis and guide management.\u003c/p\u003e","manuscriptTitle":"A Case of UMOD-Associated Nephropathy Mimicking Focal Segmental Glomerulosclerosis in a Young Male with a Positive Family History","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 16:28:07","doi":"10.21203/rs.3.rs-7969434/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-05T07:21:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-29T22:24:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"15247174327659863651655790603150073024","date":"2025-12-29T20:14:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-18T15:19:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-14T02:26:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294615989770111069007067956884989279805","date":"2025-11-09T23:30:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"312949294251276328737153858521783867236","date":"2025-11-07T00:53:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"95840401443728662156120177685499457236","date":"2025-11-06T22:19:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-06T21:51:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-06T21:26:23+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-05T07:30:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-04T18:00:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-11-04T17:57:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0321420b-561c-4848-bc3d-4b40e2f9b3e2","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:24:35+00:00","versionOfRecord":{"articleIdentity":"rs-7969434","link":"https://doi.org/10.1186/s12882-026-04924-y","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2026-03-26 16:12:39","publishedOnDateReadable":"March 26th, 2026"},"versionCreatedAt":"2025-11-18 16:28:07","video":"","vorDoi":"10.1186/s12882-026-04924-y","vorDoiUrl":"https://doi.org/10.1186/s12882-026-04924-y","workflowStages":[]},"version":"v1","identity":"rs-7969434","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7969434","identity":"rs-7969434","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}