Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants

Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants | 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 Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants Xiaoyan Zhang, Shi Jin, Xuantong Dai, Chenlin Yao, Ziyi Zhao, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7858921/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Jan, 2026 Read the published version in BMC Nephrology → Version 1 posted 11 You are reading this latest preprint version Abstract Background Alport syndrome represents the most prevalent inherited glomerular disease in chronic kidney disease patients. With the increased utilization of exome-based sequencing in clinical practice, pathogenic variants in Alport syndrome genes- COL4A3/COL4A4/COL4A5 have been detected in patients with more diverse clinical presentations including a proteinuria-predominant phenotype as well as kidney failure of unknown etiology. Complexity also rises when COL4A3/COL4A4/COL4A5 variants are co-inherited with pathogenic variants in other genetic kidney diseases. Case presentation We reported a 31-year-old male presented with kidney failure, prominent proteinuria, familial hematuria and hyperlipidemia. Whole exome sequencing detected two pathogenic variants: hemizygous COL4A5 (p.Gly702Asp) and heterozygous APOE Kyoto (p.Arg43Cys), which prompted the need for a kidney biopsy to confirm the co-occurrence of Alport syndrome and lipoprotein glomerulopathy (LPG). Biopsy findings revealed Alport syndrome histological finding with no LPG-related lesions observed. Cascade screening revealed APOE Kyoto variant in the patient’s father and elder-sister, neither of whom had proteinuria, indicating incomplete penetrance of APOE Kyoto variant in this pedigree. Conclusion This case underscores the utility of kidney biopsy as complementary to the "exome-first" approach for atypical Alport syndrome cases with complex genetic mechanism and also shed light on the incomplete penetrance of APOE Kyoto variant which is not uncommon in Chinese carriers. Alport syndrome COL4A5 APOE Kyoto exome sequencing kidney biopsy Figures Figure 1 Figure 2 Figure 3 Introduction Genetic testing has been revolutionizing the diagnosis and management of genetic kidney disease (GKD). Currently, using next generation sequencing strategies including customized gene panel sequencing, whole exome sequencing (WES) and whole genome sequencing, the diagnostic yields of GKD among pediatric or early-onset and adult-onset chronic kidney disease (CKD) patients are up to 65%[ 1 ] and 9.3%~25%[ 2 – 4 ] respectively. Among all known causative genes of GKD except for polycystic kidney disease, Alport syndrome (AS) genes- COL4A3/COL4A4/COL4A5 ( COL4A3/4/5 ) are among the most frequently identified GKD genes in both pediatric and adult CKD patients[ 2 , 5 ] and the clinical spectrum of kidney diseases associated with COL4A3/4/5 has expanded, ranging from isolated hematuria, progressive loss of kidney function with or without sensorineural hearing loss and ocular defects, to a more proteinuria-predominant phenotype such as focal segmental glomerulosclerosis (FSGS)[ 6 ]. To make things more complicated, cases with co-inheritance of COL4A3/4/5 variants and pathogenic variants in other genetic kidney diseases or AS patients with concomitant primary or secondary kidney diseases have been increasingly reported[ 7 ], under which circumstances, kidney biopsy cannot be obliviated for deciphering the disease cause. We herein described a 31-year-old male patient with the hallmark clinical presentation of kidney failure, prominent proteinuria, familial hematuria and hyperlipidemia. WES detected two pathogenic variants: COL4A5 (p.Gly702Asp) and APOE Kyoto (p.Arg43Cys) in this patient and subsequent kidney biopsy confirmed the diagnosis of AS and incomplete penetrance of APOE Kyoto variant with no lipoprotein glomerulopathy (LPG)-related histological findings observed. Case presentation A 31-year-old male patient was admitted to our hospital with exercise-induced rhabdomyolysis and an elevated serum creatinine ranging from 3.02mg/dl to 3.52mg/dl (reference range 0.49-1.30mg/dl). Following fluid replacement and urine alkalinization, serum creatinine remained at 2.51 mg/dl with an estimated glomerular filtration rate (eGFR) of 33 ml/min/1.73m 2 . Laboratory testing also revealed glomerular microscopic hematuria, nephrotic-range proteinuria of 3.75g/24h and normal range of serum albumin (41 g/L, reference range 35–55 g/L). Lipid panel showed combined hyperlipidemia (triglycerides 3.23 mmol/L, reference range < 2.5 mmol/L; total cholesterol 5.37 mmol/L, reference range < 3.6 mmol/L; LDL 3.13 mmol/L). Ultrasound of the urinary system was unremarkable. The patient had a 2-year history of hypertension and the body mass index was 29 kg/m 2 . No extra-renal manifestations were present. Familial glomerular hematuria was notable in his 33-year-old sister and mother and his father also had combined hyperlipidemia but without urine abnormalities. Therefore, WES was ordered and a hemizygous COL4A5 pathogenic variant (c.2105G > A; p.Gly702Asp) and a heterozygous APOE variant (c.127C > T; p.Arg43Cys), also named as APOE Kyoto[ 8 ] were identified in this patient. COL4A5 (p.Gly702Asp) was inherited from the patient’s mother and APOE Kyoto variant was inherited from the patient’s father (Fig. 1 ). APOE genotyping [ 9 ] revealed ε3/ε4 in both the patient and his sister, ε3/ε3 in the patient’s mother and ε2/ε4 in the patient’s father. The co-inheritance of both variants in this patient prompted a kidney biopsy to clarify whether AS and LPG co-occurred. Light microscopy (LM) was consistent with FSGS with global sclerosis in 4/7 glomeruli. Cellular proliferation or lipid droplet were not observed. No myoglobin casts were identified and moderate tubular atrophy and interstitial fibrosis were present. Vascular changes included arteriolar hyalinosis and intimal fibrosis causing luminal stenosis. Oil Red O staining was negative. Immunofluorescence revealed segmental granular mesangial C3 deposition. Electronic microscopy demonstrated uneven glomerular basement membrane (GBM) thickness with irregular thick and thin segments and partial effacement of podocyte foot process. No electron dense deposits or lipoprotein thrombi were observed (Fig. 2 ). The above histological findings supported the diagnosis of AS and incomplete penetrance of APOE Kyoto variant in this patient. Thus, the patient was given triple therapy of valsartan/dapagliflozin/finerenone along with fenofibrate and atorvastatin. During the subsequent 6-month follow-up, lipid profiles all improved and eGFR increased to 37 ml/min/1.73m 2 , whereas the reduction of proteinuria was minimal (Fig. 3 ). Discussion Different from co-occurrent AS and LPG case described previously demonstrating typical phenotypes of both diseases[ 10 ], the co-inheritance of APOE Kyoto variant in our X-linked Alport syndrome (XLAS) case apparently didn’t have an additive effect on AS phenotype as kidney biopsy indicated incomplete penetrance of APOE Kyoto variant. Our case illustrated the correct diagnostic workup of a patient with suspected GKD favoring genetic testing prior to kidney biopsy. Otherwise, APOE Kyoto variant might be missed if a physician orders phenotype-driven panel sequencing not including the APOE gene or simply orders COL4A3/4/5 Sanger sequencing based on the histological characteristics of AS. Current guidelines[ 11 ] recommend that in patients presenting with CKD or kidney failure and a family history of kidney disease or extra-renal features predictive of GKD, genetic testing should be considered as the first-line diagnostic tool since a growing number of evidences supported the diagnostic utility of genetic testing paradigms such as WES and panel sequencing in suspected monogenic CKD patients. In particular, genetic testing has high diagnostic yields of 30%~40% in patients with undetermined kidney disease who undergo kidney biopsy with inconclusive morphological diagnosis or kidney biopsy is contraindicate[ 12 ]. Exome sequencing has also illustrated the power of detecting phenocopies in clinically presumed GKD patients with the most frequent phenocopies associated with AS presenting clinically as FSGS, which is cardinal LM diagnosis of our XLAS patient[ 13 ]. In view of the above evidences, there is an ongoing discussion in the nephrology community as to what extent and in which scenarios genetic testing can replace kidney biopsy. In our case with the exceptional co-inheritance of two pathogenic variants in two distinct GKD, kidney biopsy is warranted as whether AS and LPG co-occurred needed to be confirmed not only because the patient presented with the overlapping symptoms of both diseases such as prominent proteinuria and kidney failure, but also because the incomplete penetrance of APOE Kyoto among Chinese carriers is rather high[ 14 ] (approximately 45%) and therefore, whether APOE Kyoto modified the phenotype of AS in our XLAS patient needed to be determined. COL4A5 variant types, clinical and pathological factors such as proteinuria, hearing loss and type IV α5 expression on the GBM have been established as the factors altering the disease progression of XLAS[ 15 ]. Apart from those, modified gene variants as well as co-occurrent primary or secondary kidney diseases may also explain the steeper eGFR slope in some XLAS patients. APOE is an important apolipoprotein that plays a central role in lipoprotein metabolism. Abnormal lipoprotein metabolism caused by APOE mutation may lead to APOE -related glomerular disease including APOE2 homozygous glomerulopathy and LPG caused by heterozygous APOE mutations[ 9 ]. LPG is a rare renal disorder characterized by lipid deposition in the glomeruli and tubular epithelial cells demonstrating moderate to severe proteinuria, hematuria as well as progressive kidney failure clinically. Therefore, LPG with mild dyslipidemia or normal levels of lipid which is the case in our pedigree, sometimes mimic AS at first glance clinically. To make things more complicated, the co-existence of LPG and primary or secondary glomerulopathies (IgA nephropathy[ 16 ], AS[ 10 ] and collagen type III glomerulopathy[ 17 ]) existed in Chinese patients since the majority of LPG cases were reported in Asia and APOE Kyoto variant is the major mutant in China[ 14 ]. Similar to our pedigree, in a previous reported case of APOE Kyoto LPG co-occurred with collagen type III glomerulopathy, three family members carrying APOE Kyoto variant didn’t have LPG-related clinical phenotype[ 17 ]. The hypnosis is that the local kidney microenvironment, defective macrophages, oxidative stress and environmental factors may contribute to the full-blown clinical presentation of LPG[ 18 ]. Finerenone added to angiotensin receptor antagonist (ARB)/sodium-glucose cotransporter 2 (SGLT2) blockade demonstrated the efficacy in reducing proteinuria and attenuating CKD progression in a preclinical trial in mice with AS[ 19 ]. More recently, a pilot study conducted in four AS patients also suggested that finerenone induces an appreciable reduction in proteinuria on top of dual RAS/SGLT2 blockade[ 20 ]. Thus, with the aim of reducing proteinuria and delaying kidney function deterioration, we initiated triple RAS/SGLT2/MR blockage with close monitoring of eGFR changes and serum potassium levels. Improvement of eGFR and lipid profile were observed while proteinuria remained prominent at a follow-up of 6 months. Anyhow, whether finerenone can be added to a RAS inhibitor and an SGLT2 inhibitor for treatment of AS still awaits results from prospective large scale randomized studies. In conclusion, our case highlights the integration of WES and kidney biopsy for resolving the diagnostic confusion in AS cases with complex genetic mechanism. Clinicians should take into account of the incomplete penetrance of APOE Kyoto variant which is not uncommon in Chinese carriers and warrants long-term follow-up. Abbreviations GKD Genetic kidney disease WES Whole exome sequencing CKD Chronic kidney disease AS Alport syndrome FSGS Focal segmental glomerulosclerosis LPG Lipoprotein glomerulopathy eGFR Estimated glomerular filtration rate LM Light microscopy GBM Glomerular basement membrane HE Hematoxylin-eosin PAS Periodic acid- Schiff sCr Serum creatinine TC Ttotal cholesterol TG Triglycerides XLAS X-linked Alport syndrome ARB Angiotensin receptor antagonist SGLT2 Sodium-glucose cotransporter 2 inhibitors Declarations Acknowledgments We thank the patient and his family for collaborating on this report. Author Contributions X.Y.Z. and S.J. wrote the manuscript. F.J.L. and Y.Q.S. reviewed and edited the final version. S.J. provided pathology images used in Figs. 2 and 3; Y.Q.S. also contributed to the clinical follow-up of the patient. X.T.D, C.L.Y and Z.Y.Z were responsible for data collection. All authors reviewed and approved the final manuscript. Funding This study was supported by the SJTU Research Physician Fund (2024), the National Natural Science Foundation of China Fund (82470706, 82470761, 82500817), the Shanghai Scientific and Technological Committee Fund (24YF2727300, 25ZR1402064) and the Construction Project of the “Discipline Peak Climbing Plan” of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine (XKPF2024B301). Data availability The datasets generated and/or analysed during the current study are available in the [PRJCA048559] repository, [BIG Sub - BioProject (cncb.ac.cn)] Consent to participate The present work was conducted in accordance with the Declaration of Helsinki and informed consent was obtained from the patient. Consent for publication Written informed consent for publication of their clinical details was obtained from the patient. Ethics statement The study was approved by the Institutional Review Board (or Ethics Committee) of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-C-2024-185-2). Competing interests The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References Domingo-Gallego A,et al.Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. Nephrol Dial Transplant.2022; 37(4):687-696 Groopman EE,et al.Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med.2019; 380(2):142-151 Dahl NK,et al.The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease. J Am Soc Nephrol.2023; 34(12):2039-2050 Doreille A,et al.Exome-First Strategy in Adult Patients With CKD: A Cohort Study. Kidney Int Rep.2023; 8(3):596-605 Rao J,et al.Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system. Clin Genet.2019; 96(5):402-410 Savige J,et al.Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3-COL4A5) and Their Association With Other Kidney Conditions: A Review. Am J Kidney Dis.2021; 78(6):857-864 Deltas C,et al.Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice. Genes (Basel).2023; 14(9) Li MS,et al.An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne).2022; 9:905007 Saito T,et al.Apolipoprotein E-related glomerular disorders. Kidney Int.2020; 97(2):279-288 Yang L,et al.First patient diagnosed with lipoprotein glomerulopathy and Alport syndrome. Nephrology (Carlton).2024; 29(12):985-989 Franceschini N,et al.Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group. Am J Kidney Dis.2024; 84(6):751-766 Robert T,et al.Beyond the kidney biopsy: genomic approach to undetermined kidney diseases. Clin Kidney J.2024; 17(1):sfad099 Riedhammer KM,et al.Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies. Am J Kidney Dis.2020; 76(4):460-470 Hu Z,et al.Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int.2014; 85(2):416-424 Torra R,et al.Diagnosis, management and treatment of the Alport syndrome - 2024 guideline on behalf of ERKNet, ERA and ESPN. Nephrol Dial Transplant.2025; 40(6):1091-1106 Yi X,et al.Normolipidemic lipoprotein glomerulopathy with IgA nephropathy - ApoE Kyoto mutation: a case report. Diagn Pathol.2025; 20(1):36 Liu H,et al.The first case of lipoprotein glomerulopathy complicated with collagen type III glomerulopathy and literature review. J Nephrol.2023; 36(3):663-667 Qin Y,et al.Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy. Ren Fail.2024; 46(1):2332491 Zhu Z,et al.Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice. J Am Soc Nephrol.2023; 34(9):1513-1520 Song ZR,et al.Protective Effects of Selective Mineralocorticoid Receptor Antagonist in Alport Syndrome on Top of Renin-Angiotensin-System/ Sodium-Glucose Transporter 2 Blockade. Kidney Int Rep.2024; 9(3):730-731 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 29 Jan, 2026 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 03 Dec, 2025 Reviews received at journal 17 Nov, 2025 Reviews received at journal 13 Nov, 2025 Reviewers agreed at journal 07 Nov, 2025 Reviewers agreed at journal 05 Nov, 2025 Reviewers agreed at journal 04 Nov, 2025 Reviewers invited by journal 04 Nov, 2025 Editor assigned by journal 04 Nov, 2025 Editor invited by journal 27 Oct, 2025 Submission checks completed at journal 24 Oct, 2025 First submitted to journal 24 Oct, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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07:16:52","extension":"xml","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":47086,"visible":true,"origin":"","legend":"","description":"","filename":"37931bc5b1af49409b33afdf37139a8b1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7858921/v1/f101590fec15df61cbfb12e9.xml"},{"id":95910042,"identity":"0fd74d5a-2938-4f5f-b405-03706d9e6da9","added_by":"auto","created_at":"2025-11-14 10:09:30","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54734,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7858921/v1/0ca98e6f6af96c96c89ad467.html"},{"id":96243352,"identity":"06bb3909-8090-4338-87b2-a5c5e6d533ec","added_by":"auto","created_at":"2025-11-19 07:16:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4891541,"visible":true,"origin":"","legend":"\u003cp\u003eFamily pedigree with clinical phenotypes \u003cstrong\u003e(a)\u003c/strong\u003eand sequencing chromatograms \u003cstrong\u003e(b)\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7858921/v1/88d0b09dfb496e54c5116fe4.png"},{"id":95910048,"identity":"988a8d39-7e63-46cf-8cf6-c7467a89f556","added_by":"auto","created_at":"2025-11-14 10:09:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26523393,"visible":true,"origin":"","legend":"\u003cp\u003eKidney biopsy findings. \u003cstrong\u003e(a)\u003c/strong\u003e diffuse interstitial inflammation and tubular atrophy (hematoxylin-eosin [HE]×200); \u003cstrong\u003e(b)\u003c/strong\u003e segmental sclerosis (periodic acid- Schiff [PAS]×400); \u003cstrong\u003e(c)\u003c/strong\u003e negative oil-red O staining on frozen section; \u003cstrong\u003e(d)\u003c/strong\u003e uneven GBM thickness without electron dense deposits or lipoprotein thrombi under electron microscopy. \u003cstrong\u003e(e)\u003c/strong\u003e thin GBM under electron microscopy.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7858921/v1/df296d5d065b00f5ad56e166.png"},{"id":96242984,"identity":"9320521c-3e0f-4144-89f0-82c63f5c42ac","added_by":"auto","created_at":"2025-11-19 07:15:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2541817,"visible":true,"origin":"","legend":"\u003cp\u003eLongitudinal follow-up of clinical parameters in the patient. \u003cstrong\u003e(a)\u003c/strong\u003e Changes in serum creatinine, estimated glomerular filtration rate (eGFR), and proteinuria during the subsequent 6-month follow-up.\u003cstrong\u003e (b)\u003c/strong\u003eChanges in total cholesterol (TC), triglycerides (TG), LDL-C, and ApoE levels during the subsequent 6-month follow-up.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7858921/v1/0547432cacc74b68e3c59dba.png"},{"id":101690818,"identity":"cbf3e50b-aa6b-49e6-9070-8dc282a44c4c","added_by":"auto","created_at":"2026-02-02 16:09:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":31708077,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7858921/v1/3d9f5821-279c-4099-9165-2ac50573a794.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGenetic testing has been revolutionizing the diagnosis and management of genetic kidney disease (GKD). Currently, using next generation sequencing strategies including customized gene panel sequencing, whole exome sequencing (WES) and whole genome sequencing, the diagnostic yields of GKD among pediatric or early-onset and adult-onset chronic kidney disease (CKD) patients are up to 65%[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and 9.3%~25%[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] respectively.\u003c/p\u003e\u003cp\u003eAmong all known causative genes of GKD except for polycystic kidney disease, Alport syndrome (AS) genes-\u003cem\u003eCOL4A3/COL4A4/COL4A5\u003c/em\u003e(\u003cem\u003eCOL4A3/4/5\u003c/em\u003e) are among the most frequently identified GKD genes in both pediatric and adult CKD patients[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and the clinical spectrum of kidney diseases associated with \u003cem\u003eCOL4A3/4/5\u003c/em\u003e has expanded, ranging from isolated hematuria, progressive loss of kidney function with or without sensorineural hearing loss and ocular defects, to a more proteinuria-predominant phenotype such as focal segmental glomerulosclerosis (FSGS)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. To make things more complicated, cases with co-inheritance of \u003cem\u003eCOL4A3/4/5\u003c/em\u003e variants and pathogenic variants in other genetic kidney diseases or AS patients with concomitant primary or secondary kidney diseases have been increasingly reported[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], under which circumstances, kidney biopsy cannot be obliviated for deciphering the disease cause.\u003c/p\u003e\u003cp\u003eWe herein described a 31-year-old male patient with the hallmark clinical presentation of kidney failure, prominent proteinuria, familial hematuria and hyperlipidemia. WES detected two pathogenic variants: \u003cem\u003eCOL4A5\u003c/em\u003e (p.Gly702Asp) and \u003cem\u003eAPOE\u003c/em\u003e Kyoto (p.Arg43Cys) in this patient and subsequent kidney biopsy confirmed the diagnosis of AS and incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant with no lipoprotein glomerulopathy (LPG)-related histological findings observed.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 31-year-old male patient was admitted to our hospital with exercise-induced rhabdomyolysis and an elevated serum creatinine ranging from 3.02mg/dl to 3.52mg/dl (reference range 0.49-1.30mg/dl). Following fluid replacement and urine alkalinization, serum creatinine remained at 2.51 mg/dl with an estimated glomerular filtration rate (eGFR) of 33 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e. Laboratory testing also revealed glomerular microscopic hematuria, nephrotic-range proteinuria of 3.75g/24h and normal range of serum albumin (41 g/L, reference range 35\u0026ndash;55 g/L). Lipid panel showed combined hyperlipidemia (triglycerides 3.23 mmol/L, reference range\u0026thinsp;\u0026lt;\u0026thinsp;2.5 mmol/L; total cholesterol 5.37 mmol/L, reference range\u0026thinsp;\u0026lt;\u0026thinsp;3.6 mmol/L; LDL 3.13 mmol/L). Ultrasound of the urinary system was unremarkable. The patient had a 2-year history of hypertension and the body mass index was 29 kg/m\u003csup\u003e2\u003c/sup\u003e. No extra-renal manifestations were present.\u003c/p\u003e\u003cp\u003eFamilial glomerular hematuria was notable in his 33-year-old sister and mother and his father also had combined hyperlipidemia but without urine abnormalities. Therefore, WES was ordered and a hemizygous \u003cem\u003eCOL4A5\u003c/em\u003e pathogenic variant (c.2105G\u0026thinsp;\u0026gt;\u0026thinsp;A; p.Gly702Asp) and a heterozygous \u003cem\u003eAPOE\u003c/em\u003e variant (c.127C\u0026thinsp;\u0026gt;\u0026thinsp;T; p.Arg43Cys), also named as \u003cem\u003eAPOE\u003c/em\u003e Kyoto[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] were identified in this patient. \u003cem\u003eCOL4A5\u003c/em\u003e (p.Gly702Asp) was inherited from the patient\u0026rsquo;s mother and \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant was inherited from the patient\u0026rsquo;s father (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). \u003cem\u003eAPOE\u003c/em\u003e genotyping [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] revealed ε3/ε4 in both the patient and his sister, ε3/ε3 in the patient\u0026rsquo;s mother and ε2/ε4 in the patient\u0026rsquo;s father.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe co-inheritance of both variants in this patient prompted a kidney biopsy to clarify whether AS and LPG co-occurred. Light microscopy (LM) was consistent with FSGS with global sclerosis in 4/7 glomeruli. Cellular proliferation or lipid droplet were not observed. No myoglobin casts were identified and moderate tubular atrophy and interstitial fibrosis were present. Vascular changes included arteriolar hyalinosis and intimal fibrosis causing luminal stenosis. Oil Red O staining was negative. Immunofluorescence revealed segmental granular mesangial C3 deposition. Electronic microscopy demonstrated uneven glomerular basement membrane (GBM) thickness with irregular thick and thin segments and partial effacement of podocyte foot process. No electron dense deposits or lipoprotein thrombi were observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe above histological findings supported the diagnosis of AS and incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant in this patient. Thus, the patient was given triple therapy of valsartan/dapagliflozin/finerenone along with fenofibrate and atorvastatin. During the subsequent 6-month follow-up, lipid profiles all improved and eGFR increased to 37 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e, whereas the reduction of proteinuria was minimal (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDifferent from co-occurrent AS and LPG case described previously demonstrating typical phenotypes of both diseases[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the co-inheritance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant in our X-linked Alport syndrome (XLAS) case apparently didn\u0026rsquo;t have an additive effect on AS phenotype as kidney biopsy indicated incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant. Our case illustrated the correct diagnostic workup of a patient with suspected GKD favoring genetic testing prior to kidney biopsy. Otherwise, \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant might be missed if a physician orders phenotype-driven panel sequencing not including the \u003cem\u003eAPOE\u003c/em\u003e gene or simply orders \u003cem\u003eCOL4A3/4/5\u003c/em\u003e Sanger sequencing based on the histological characteristics of AS.\u003c/p\u003e\u003cp\u003eCurrent guidelines[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] recommend that in patients presenting with CKD or kidney failure and a family history of kidney disease or extra-renal features predictive of GKD, genetic testing should be considered as the first-line diagnostic tool since a growing number of evidences supported the diagnostic utility of genetic testing paradigms such as WES and panel sequencing in suspected monogenic CKD patients. In particular, genetic testing has high diagnostic yields of 30%~40% in patients with undetermined kidney disease who undergo kidney biopsy with inconclusive morphological diagnosis or kidney biopsy is contraindicate[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Exome sequencing has also illustrated the power of detecting phenocopies in clinically presumed GKD patients with the most frequent phenocopies associated with AS presenting clinically as FSGS, which is cardinal LM diagnosis of our XLAS patient[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In view of the above evidences, there is an ongoing discussion in the nephrology community as to what extent and in which scenarios genetic testing can replace kidney biopsy. In our case with the exceptional co-inheritance of two pathogenic variants in two distinct GKD, kidney biopsy is warranted as whether AS and LPG co-occurred needed to be confirmed not only because the patient presented with the overlapping symptoms of both diseases such as prominent proteinuria and kidney failure, but also because the incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto among Chinese carriers is rather high[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] (approximately 45%) and therefore, whether \u003cem\u003eAPOE\u003c/em\u003e Kyoto modified the phenotype of AS in our XLAS patient needed to be determined.\u003c/p\u003e\u003cp\u003e\u003cem\u003eCOL4A5\u003c/em\u003e variant types, clinical and pathological factors such as proteinuria, hearing loss and type IV α5 expression on the GBM have been established as the factors altering the disease progression of XLAS[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Apart from those, modified gene variants as well as co-occurrent primary or secondary kidney diseases may also explain the steeper eGFR slope in some XLAS patients. \u003cem\u003eAPOE\u003c/em\u003e is an important apolipoprotein that plays a central role in lipoprotein metabolism. Abnormal lipoprotein metabolism caused by \u003cem\u003eAPOE\u003c/em\u003e mutation may lead to \u003cem\u003eAPOE\u003c/em\u003e-related glomerular disease including \u003cem\u003eAPOE2\u003c/em\u003e homozygous glomerulopathy and LPG caused by heterozygous \u003cem\u003eAPOE\u003c/em\u003e mutations[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. LPG is a rare renal disorder characterized by lipid deposition in the glomeruli and tubular epithelial cells demonstrating moderate to severe proteinuria, hematuria as well as progressive kidney failure clinically. Therefore, LPG with mild dyslipidemia or normal levels of lipid which is the case in our pedigree, sometimes mimic AS at first glance clinically. To make things more complicated, the co-existence of LPG and primary or secondary glomerulopathies (IgA nephropathy[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], AS[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and collagen type III glomerulopathy[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]) existed in Chinese patients since the majority of LPG cases were reported in Asia and \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant is the major mutant in China[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Similar to our pedigree, in a previous reported case of \u003cem\u003eAPOE\u003c/em\u003e Kyoto LPG co-occurred with collagen type III glomerulopathy, three family members carrying \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant didn\u0026rsquo;t have LPG-related clinical phenotype[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The hypnosis is that the local kidney microenvironment, defective macrophages, oxidative stress and environmental factors may contribute to the full-blown clinical presentation of LPG[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFinerenone added to angiotensin receptor antagonist (ARB)/sodium-glucose cotransporter 2 (SGLT2) blockade demonstrated the efficacy in reducing proteinuria and attenuating CKD progression in a preclinical trial in mice with AS[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. More recently, a pilot study conducted in four AS patients also suggested that finerenone induces an appreciable reduction in proteinuria on top of dual RAS/SGLT2 blockade[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Thus, with the aim of reducing proteinuria and delaying kidney function deterioration, we initiated triple RAS/SGLT2/MR blockage with close monitoring of eGFR changes and serum potassium levels. Improvement of eGFR and lipid profile were observed while proteinuria remained prominent at a follow-up of 6 months. Anyhow, whether finerenone can be added to a RAS inhibitor and an SGLT2 inhibitor for treatment of AS still awaits results from prospective large scale randomized studies.\u003c/p\u003e\u003cp\u003eIn conclusion, our case highlights the integration of WES and kidney biopsy for resolving the diagnostic confusion in AS cases with complex genetic mechanism. Clinicians should take into account of the incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant which is not uncommon in Chinese carriers and warrants long-term follow-up.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGKD \u0026nbsp; \u0026nbsp; \u0026nbsp; Genetic kidney disease\u003c/p\u003e\n\u003cp\u003eWES \u0026nbsp; \u0026nbsp; \u0026nbsp; Whole exome sequencing\u003c/p\u003e\n\u003cp\u003eCKD \u0026nbsp; \u0026nbsp; \u0026nbsp; Chronic kidney disease\u003c/p\u003e\n\u003cp\u003eAS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Alport syndrome\u003c/p\u003e\n\u003cp\u003eFSGS \u0026nbsp; \u0026nbsp; \u0026nbsp;Focal segmental glomerulosclerosis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLPG \u0026nbsp; \u0026nbsp; \u0026nbsp; Lipoprotein glomerulopathy\u003c/p\u003e\n\u003cp\u003eeGFR \u0026nbsp; \u0026nbsp; \u0026nbsp;Estimated glomerular filtration rate\u003c/p\u003e\n\u003cp\u003eLM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Light microscopy\u003c/p\u003e\n\u003cp\u003eGBM \u0026nbsp; \u0026nbsp; \u0026nbsp;Glomerular basement membrane\u003c/p\u003e\n\u003cp\u003eHE \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hematoxylin-eosin\u003c/p\u003e\n\u003cp\u003ePAS \u0026nbsp; \u0026nbsp; \u0026nbsp; Periodic acid- Schiff\u0026nbsp;\u003c/p\u003e\n\u003cp\u003esCr \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Serum creatinine\u003c/p\u003e\n\u003cp\u003eTC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ttotal cholesterol\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTG \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Triglycerides\u003c/p\u003e\n\u003cp\u003eXLAS \u0026nbsp; \u0026nbsp; \u0026nbsp;X-linked Alport syndrome\u003c/p\u003e\n\u003cp\u003eARB \u0026nbsp; \u0026nbsp; \u0026nbsp; Angiotensin receptor antagonist\u003c/p\u003e\n\u003cp\u003eSGLT2 \u0026nbsp; \u0026nbsp; Sodium-glucose cotransporter 2 inhibitors\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patient and his family for collaborating on this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.Y.Z. and S.J. wrote the manuscript. F.J.L. and Y.Q.S. reviewed and edited the final version. S.J. provided pathology images used in Figs. 2 and 3; Y.Q.S. also contributed to the clinical follow-up of the patient. X.T.D, C.L.Y and Z.Y.Z were responsible for data collection. All authors reviewed and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the SJTU Research Physician Fund (2024), the National Natural Science Foundation of China Fund (82470706, 82470761, 82500817), the Shanghai Scientific and Technological Committee Fund (24YF2727300, 25ZR1402064) and the Construction Project of the \u0026ldquo;Discipline Peak Climbing Plan\u0026rdquo; of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine (XKPF2024B301).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available in the [PRJCA048559] repository, [BIG Sub - BioProject (cncb.ac.cn)]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present work was conducted in accordance with the Declaration of Helsinki and informed consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of their clinical details was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was\u0026nbsp;approved by the Institutional Review Board (or Ethics Committee) of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-C-2024-185-2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePublisher\u0026rsquo;s note\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDomingo-Gallego A,et al.Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. Nephrol Dial Transplant.2022; 37(4):687-696\u003c/li\u003e\n\u003cli\u003eGroopman EE,et al.Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med.2019; 380(2):142-151\u003c/li\u003e\n\u003cli\u003eDahl NK,et al.The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease. J Am Soc Nephrol.2023; 34(12):2039-2050\u003c/li\u003e\n\u003cli\u003eDoreille A,et al.Exome-First Strategy in Adult Patients With CKD: A Cohort Study. Kidney Int Rep.2023; 8(3):596-605\u003c/li\u003e\n\u003cli\u003eRao J,et al.Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system. Clin Genet.2019; 96(5):402-410\u003c/li\u003e\n\u003cli\u003eSavige J,et al.Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3-COL4A5) and Their Association With Other Kidney Conditions: A Review. Am J Kidney Dis.2021; 78(6):857-864\u003c/li\u003e\n\u003cli\u003eDeltas C,et al.Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice. Genes (Basel).2023; 14(9)\u003c/li\u003e\n\u003cli\u003eLi MS,et al.An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne).2022; 9:905007\u003c/li\u003e\n\u003cli\u003eSaito T,et al.Apolipoprotein E-related glomerular disorders. Kidney Int.2020; 97(2):279-288\u003c/li\u003e\n\u003cli\u003eYang L,et al.First patient diagnosed with lipoprotein glomerulopathy and Alport syndrome. Nephrology (Carlton).2024; 29(12):985-989\u003c/li\u003e\n\u003cli\u003eFranceschini N,et al.Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group. Am J Kidney Dis.2024; 84(6):751-766\u003c/li\u003e\n\u003cli\u003eRobert T,et al.Beyond the kidney biopsy: genomic approach to undetermined kidney diseases. Clin Kidney J.2024; 17(1):sfad099\u003c/li\u003e\n\u003cli\u003eRiedhammer KM,et al.Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies. Am J Kidney Dis.2020; 76(4):460-470\u003c/li\u003e\n\u003cli\u003eHu Z,et al.Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int.2014; 85(2):416-424\u003c/li\u003e\n\u003cli\u003eTorra R,et al.Diagnosis, management and treatment of the Alport syndrome - 2024 guideline on behalf of ERKNet, ERA and ESPN. Nephrol Dial Transplant.2025; 40(6):1091-1106\u003c/li\u003e\n\u003cli\u003eYi X,et al.Normolipidemic lipoprotein glomerulopathy with IgA nephropathy - ApoE Kyoto mutation: a case report. Diagn Pathol.2025; 20(1):36\u003c/li\u003e\n\u003cli\u003eLiu H,et al.The first case of lipoprotein glomerulopathy complicated with collagen type III glomerulopathy and literature review. J Nephrol.2023; 36(3):663-667\u003c/li\u003e\n\u003cli\u003eQin Y,et al.Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy. Ren Fail.2024; 46(1):2332491\u003c/li\u003e\n\u003cli\u003eZhu Z,et al.Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice. J Am Soc Nephrol.2023; 34(9):1513-1520\u003c/li\u003e\n\u003cli\u003eSong ZR,et al.Protective Effects of Selective Mineralocorticoid Receptor Antagonist in Alport Syndrome on Top of Renin-Angiotensin-System/ Sodium-Glucose Transporter 2 Blockade. Kidney Int Rep.2024; 9(3):730-731\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":"Alport syndrome, COL4A5, APOE Kyoto, exome sequencing, kidney biopsy","lastPublishedDoi":"10.21203/rs.3.rs-7858921/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7858921/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAlport syndrome represents the most prevalent inherited glomerular disease in chronic kidney disease patients. With the increased utilization of exome-based sequencing in clinical practice, pathogenic variants in Alport syndrome genes-\u003cem\u003eCOL4A3/COL4A4/COL4A5\u003c/em\u003e have been detected in patients with more diverse clinical presentations including a proteinuria-predominant phenotype as well as kidney failure of unknown etiology. Complexity also rises when \u003cem\u003eCOL4A3/COL4A4/COL4A5\u003c/em\u003e variants are co-inherited with pathogenic variants in other genetic kidney diseases.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e\u003cp\u003eWe reported a 31-year-old male presented with kidney failure, prominent proteinuria, familial hematuria and hyperlipidemia. Whole exome sequencing detected two pathogenic variants: hemizygous \u003cem\u003eCOL4A5\u003c/em\u003e (p.Gly702Asp) and heterozygous \u003cem\u003eAPOE\u003c/em\u003e Kyoto (p.Arg43Cys), which prompted the need for a kidney biopsy to confirm the co-occurrence of Alport syndrome and lipoprotein glomerulopathy (LPG). Biopsy findings revealed Alport syndrome histological finding with no LPG-related lesions observed. Cascade screening revealed \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant in the patient\u0026rsquo;s father and elder-sister, neither of whom had proteinuria, indicating incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant in this pedigree.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis case underscores the utility of kidney biopsy as complementary to the \"exome-first\" approach for atypical Alport syndrome cases with complex genetic mechanism and also shed light on the incomplete penetrance of \u003cem\u003eAPOE\u003c/em\u003e Kyoto variant which is not uncommon in Chinese carriers.\u003c/p\u003e","manuscriptTitle":"Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-14 10:09:24","doi":"10.21203/rs.3.rs-7858921/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-03T09:49:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-17T18:42:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-13T09:41:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332336914557711971052001689244653718476","date":"2025-11-08T00:26:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56004506437919735582526073174442541502","date":"2025-11-05T17:50:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294615989770111069007067956884989279805","date":"2025-11-05T04:29:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-05T04:27:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-04T05:38:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-27T05:24:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-24T08:10:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-10-24T08:07:09+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":"b6f78cf2-ba65-4339-8a76-3773107ec217","owner":[],"postedDate":"November 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:05:37+00:00","versionOfRecord":{"articleIdentity":"rs-7858921","link":"https://doi.org/10.1186/s12882-026-04775-7","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2026-01-29 15:59:18","publishedOnDateReadable":"January 29th, 2026"},"versionCreatedAt":"2025-11-14 10:09:24","video":"","vorDoi":"10.1186/s12882-026-04775-7","vorDoiUrl":"https://doi.org/10.1186/s12882-026-04775-7","workflowStages":[]},"version":"v1","identity":"rs-7858921","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7858921","identity":"rs-7858921","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}