Background: Genetic causes of chronic diseases, once considered rare in adult-onset disease, now account for between 10 and 20% of cases of chronic kidney disease (CKD). Confirming a genetic diagnosis can influence disease management; however, the utility of genetic testing in older adults remains poorly understood, partly due to age-based restrictions on testing access. To better evaluate the diagnostic yield and clinical utility of genetic testing in this population, we analyzed data from adults aged ≥50 years with CKD who were assessed in a specialized kidney genetics clinic. Methods: We studied a cohort of 125 adults with CKD aged ≥50 years at the time of genetic testing. Genetic testing included gene panels targeting disease-related genes based on clinical phenotype, and/or exome sequencing for additional monogenic causes if the initial panel testing was inconclusive. Results: Pathogenic variants in disease-related genes were identified in 38% of patients. The highest diagnostic yield (48%) was in patients aged 50-54 years. The most common diagnosis post-testing was glomerulopathies (32%). Clinical utility, shown through the case series, included modifications to treatment and clinical management, as well as a reduction in the diagnostic odyssey. Conclusions: Our findings from a dedicated Kidney Genetics Clinic show that genetic testing in adults ≥50 years with CKD has significant diagnostic and clinical utility. These results support guideline recommendations that there should be no upper age limit for genetic testing. Future research in unselected CKD populations is needed to establish the broader applicability and feasibility of genetic testing in older adults.

Department of Biochemistry Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Department of Clinical Neurological Sciences Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Department of Endocrinology and Metabolism Sciences Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Department of Epidemiology and Biostatistics Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Department of Medicine Division of Geriatric Medicine Sciences Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Department of Medicine Division of Nephrology London Health Sciences Centre London ON N6A 5A5 Canada

Department of Medicine Division of Nephrology Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Department of Medicine Division of Rheumatology Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 5C1 Canada

Division of Medical Genetics Department of Pediatrics Victoria Hospital London Health Science Center 800 Commissioners Rd E London ON N6A 5W9 Canada

Multi Organ Transplant Program London Health Sciences Centre London ON N6A 5A5 Canada

Population Health Research Institute 20 Copeland Avenue Hamilton ON L8L 2X2 Canada

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University CZ 121 08 Prague Czech Republic

Robarts Research Institute Schulich School of Medicine and Dentistry Western University 1151 Richmond St London ON N6A 3K7 Canada

Section on Nephrology Wake Forest School of Medicine Winston Salem NC 27157 USA

Zobrazit více v PubMed

Dahl N.K., Bloom M.S., Chebib F.T., Clark D., Westemeyer M., Jandeska S., Zhang Z., Milo-Rasouly H., Kolupaeva V., Marasa M., et al. The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease. J. Am. Soc. Nephrol. 2023;34:2039. doi: 10.1681/ASN.0000000000000249. PubMed DOI PMC

Groopman E.E., Marasa M., Cameron-Christie S., Petrovski S., Aggarwal V.S., Milo-Rasouly H., Li Y., Zhang J., Nestor J., Krithivasan P., et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N. Engl. J. Med. 2019;380:142–151. doi: 10.1056/NEJMoa1806891. PubMed DOI PMC

Abdulrahim J.W., Kwee L.C., Alenezi F., Sun A.Y., Baras A., Ajayi T.A., Henao R., Holley C., McGarrah R., Daubert J.P., et al. Identification of Undetected Monogenic Cardiovascular Disorders. J. Am. Coll. Cardiol. 2020;76:797–808. doi: 10.1016/j.jacc.2020.06.037. PubMed DOI PMC

Van Der Lee S.J., Hulsman M., Van Spaendonk R., Van Der Schaar J., Dijkstra J., Tesi N., van Ruissen F., Elting M., Reinders M., De Rojas I., et al. Prevalence of Pathogenic Variants and Eligibility Criteria for Genetic Testing in Patients Who Visit a Memory Clinic. Neurology. 2025;104:e210273. doi: 10.1212/WNL.0000000000210273. PubMed DOI PMC

Ganapathy A., Mishra A., Soni M.R., Kumar P., Sadagopan M., Kanthi A.V., Patric I.R.P., George S., Sridharan A., Thyagarajan T.C., et al. Multi-gene testing in neurological disorders showed an improved diagnostic yield: Data from over 1000 Indian patients. J. Neurol. 2019;266:1919–1926. doi: 10.1007/s00415-019-09358-1. PubMed DOI

Schott C., Lebedeva V., Taylor C., Abumelha S., Roshanov P.S., Connaughton D.M. Utility of Genetic Testing in Adults with Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Clin. J. Am. Soc. Nephrol. 2024;20:101–115. doi: 10.2215/CJN.0000000000000564. PubMed DOI PMC

Elliott M.D., James L.C., Simms E.L., Sharma P., Girard L.P., Cheema K., Elliott M.J., Lauzon J.L., Chun J. Mainstreaming Genetic Testing for Adult Patients With Autosomal Dominant Polycystic Kidney Disease. Can. J. Kidney Health Dis. 2021;8:20543581211055001. doi: 10.1177/20543581211055001. PubMed DOI PMC

Ames E.G., Anand P.M., Bekheirnia M.R., Doshi M.D., El Ters M., Freese M.E., Gbadegesin R.A., Guay-Woodford L.M., Java A., Ranch D., et al. Evaluation for genetic disease in kidney transplant candidates: A practice resource. Am. J. Transplant. 2025;25:237–249. doi: 10.1016/j.ajt.2024.10.019. PubMed DOI

Aron A.W., Dahl N.K., Besse W. A Practical Guide to Genetic Testing for Kidney Disorders of Unknown Etiology. Kidney360. 2022;3:1640–1651. doi: 10.34067/KID.0007552021. PubMed DOI PMC

National Health Services England National Genomic Test Directory Testing Criteria for Rare and Inherited Disease. 2024. [(accessed on 26 March 2024)]. Available online: https://www.england.nhs.uk/wp-content/uploads/2024/07/national-genomic-test-directory-rare-and-inherited-disease-eligibility-criteria-v7.pdf.

Guidelines for Genetic Diagnostics in Kidney Disease. MEDonline Publisher; Breukelen, The Netherlands: 2018. [(accessed on 17 December 2024)]. Available online: https://publicatie.nefro.nl/richtlijnen/handreiking-genetische-diagnostiek-bij-nierziekten/

Snoek R., van Jaarsveld R.H., Nguyen T.Q., Peters E.D.J., Elferink M.G., Ernst R.F., Rookmaaker M.B., Lilien M.R., Spierings E., Goldschmeding R., et al. Genetics-first approach improves diagnostics of ESKD patients <50 years old. Nephrol. Dial. Transplant. 2022;37:349–357. doi: 10.1093/ndt/gfaa363. PubMed DOI

Vivante A., Hildebrandt F. Exploring the genetic basis of early-onset chronic kidney disease. Nat. Rev. Nephrol. 2016;12:133–146. doi: 10.1038/nrneph.2015.205. PubMed DOI PMC

Schott C., Arnaldi M., Baker C., Wang J., McIntyre A.D., Colaicovo S., Relouw S., Offerni G.A., Campagnolo C., Nyatten L.R.V., et al. Implementation of a kidney genetic service into the diagnostic pathway for patients with chronic kidney disease in Canada. Kidney Int. Rep. 2025;10:574–590. doi: 10.1016/j.ekir.2024.11.004. PubMed DOI PMC

KDIGO Conference Participants Genetics in chronic kidney disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2022;101:1126–1141. doi: 10.1016/j.kint.2022.03.019. PubMed DOI PMC

Hildebrandt F. Genetic kidney diseases. Lancet. 2010;375:1287–1295. doi: 10.1016/S0140-6736(10)60236-X. PubMed DOI PMC

Merchant A.A., Ling E. An approach to treating older adults with chronic kidney disease. CMAJ. 2023;195:E612–E618. doi: 10.1503/cmaj.221427. PubMed DOI PMC

Levey A.S., Eckardt K.-U., Tsukamoto Y., Levin A., Coresh J., Rossert J., Zeeuw D.D.E., Hostetter T.H., Lameire N., Eknoyan G. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO) Kidney Int. 2005;67:2089–2100. doi: 10.1111/j.1523-1755.2005.00365.x. PubMed DOI

Ayasreh N., Bullich G., Miquel R., Furlano M., Ruiz P., Lorente L., Valero O., García-González M.A., Arhda N., Garin I., et al. Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1. Am. J. Kidney Dis. 2018;72:411–418. doi: 10.1053/j.ajkd.2018.03.019. PubMed DOI

Blumenstiel B., DeFelice M., Birsoy O., Bleyer A.J., Kmoch S., Carter T.A., Gnirke A., Kidd K., Rehm H.L., Ronco L., et al. Development and Validation of a Mass Spectrometry-Based Assay for the Molecular Diagnosis of Mucin-1 Kidney Disease. J. Mol. Diagn. 2016;18:566–571. doi: 10.1016/j.jmoldx.2016.03.003. PubMed DOI

Szuto A. Genome-Wide Sequencing Ontario. 2023. Provincial Update: Exome Sequencing for Rare Disease Diagnostics. [(accessed on 15 July 2024)]. Available online: https://gsontario.ca/for-providers/patient-eligibility/

Sheikh Hassani M., Jain R., Ramaswamy S., Sinha S., El Naofal M., Halabi N., Alyafei S., Alfalasi R., Shenbagam S., Taylor A., et al. Virtual Gene Panels Have a Superior Diagnostic Yield for Inherited Rare Diseases Relative to Static Panels. Clin. Chem. 2025;71:169–184. doi: 10.1093/clinchem/hvae183. PubMed DOI

Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., et al. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015;17:405–424. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Hayeems R.Z., Dimmock D., Bick D., Belmont J.W., Green R.C., Lanpher B., Jobanputra V., Mendoza R., Kulkarni S., Grove M.E., et al. Clinical utility of genomic sequencing: A measurement toolkit. NPJ Genom. Med. 2020;5:56. doi: 10.1038/s41525-020-00164-7. PubMed DOI PMC

Ariceta G., Beck-Nielsen S.S., Boot A.M., Brandi M.L., Briot K., de Lucas Collantes C., Emma F., Giannini S., Haffner D., Keen R., et al. The International X-Linked Hypophosphatemia (XLH) Registry: First interim analysis of baseline demographic, genetic and clinical data. Orphanet J. Rare Dis. 2023;18:304. doi: 10.1186/s13023-023-02882-4. PubMed DOI PMC

Pettifor J.M. What’s new in hypophosphataemic rickets? Eur. J. Pediatr. 2008;167:493–499. doi: 10.1007/s00431-007-0662-1. PubMed DOI PMC

Kayser M., Jain P., Bale A., Carpenter T.O. A De Novo Deleterious PHEX Variant Without Clinical Features of X-Linked Hypophosphatemia. JCEM Case Rep. 2023;1:luad082. doi: 10.1210/jcemcr/luad082. PubMed DOI PMC

Giannini S., Bianchi M.L., Rendina D., Massoletti P., Lazzerini D., Brandi M.L. Burden of disease and clinical targets in adult patients with X-linked hypophosphatemia. A comprehensive review. Osteoporos. Int. 2021;32:1937–1949. doi: 10.1007/s00198-021-05997-1. PubMed DOI PMC

Haffner D., Emma F., Eastwood D.M., Duplan M.B., Bacchetta J., Schnabel D., Wicart P., Bockenhauer D., Santos F., Levtchenko E., et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat. Rev. Nephrol. 2019;15:435. doi: 10.1038/s41581-019-0152-5. PubMed DOI PMC

Emma F., Salviati L. Mitochondrial cytopathies and the kidney. Nephrol. Ther. 2017;13((Suppl. S1)):S23–S28. doi: 10.1016/j.nephro.2017.01.014. PubMed DOI

Chan S.S.L., Longley M.J., Copeland W.C. The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J. Biol. Chem. 2005;280:31341–31346. doi: 10.1074/jbc.M506762200. PubMed DOI

Parikh S., Goldstein A., Karaa A., Koenig M.K., Anselm I., Brunel-Guitton C., Christodoulou J., Cohen B.H., Dimmock D., Enns G.M., et al. Patient care standards for primary mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society. Genet. Med. 2017;19:1380. doi: 10.1038/gim.2017.107. PubMed DOI PMC

Cohen B.H., Chinnery P.F., Copeland W.C. POLG-Related Disorders. In: Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Bean L.J., Gripp K.W., Amemiya A., editors. GeneReviews®. University of Washington; Seattle, WA, USA: 1993. [(accessed on 28 May 2024)]. Available online: http://www.ncbi.nlm.nih.gov/books/NBK26471/ PubMed

Cornec-Le Gall E., Alam A., Perrone R.D. Autosomal dominant polycystic kidney disease. Lancet. 2019;393:919–935. doi: 10.1016/S0140-6736(18)32782-X. PubMed DOI

Fujimaru T., Mori T., Sekine A., Mandai S., Chiga M., Kikuchi H., Ando F., Mori Y., Nomura N., Iimori S., et al. Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease. Clin. Genet. 2018;94:125–131. doi: 10.1111/cge.13249. PubMed DOI

Senum S.R., Li Y.M., Benson K.A., Joli G., Olinger E., Lavu S., Madsen C.D., Gregory A.V., Neatu R., Kline T.L., et al. Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype. Am. J. Hum. Genet. 2022;109:136–156. doi: 10.1016/j.ajhg.2021.11.016. PubMed DOI PMC

Nuñez Zuno J.A., Khaddour K. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2024. [(accessed on 10 July 2024)]. Thrombotic Thrombocytopenic Purpura Evaluation and Management. Available online: http://www.ncbi.nlm.nih.gov/books/NBK470585/ PubMed

Tsai H.-M. The kidney in thrombotic thrombocytopenic purpura. Minerva Med. 2007;98:731–747. PubMed PMC

Dorgalaleh A., Mahmudi M., Tabibian S., Khatib Z.K., Tamaddon G.H., Moghaddam E.S., Bamedi T., Alizadeh S., Moradi E. Anemia and Thrombocytopenia in Acute and Chronic Renal Failure. Int. J. Hematol.-Oncol. Stem Cell Res. 2013;7:34–39. PubMed PMC

Živná M., Kidd K.O., Barešová V., Hůlková H., Kmoch S., Bleyer A.J. Autosomal dominant tubulointerstitial kidney disease: A review. Am. J. Med. Genet. C Semin. Med. Genet. 2022;190:309–324. doi: 10.1002/ajmg.c.32008. PubMed DOI PMC

Kmochová T., Kidd K.O., Orr A., Hnízda A., Hartmannová H., Hodaňová K., Vyleťal P., Naušová K., Brinsa V., Trešlová H., et al. Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis. Kidney Int. 2024;105:799–811. doi: 10.1016/j.kint.2023.11.021. PubMed DOI

Rasouly H.M., Balderes O., Marasa M., Fernandez H., Lipton M., Lin F., Gharavi A.G., Sabatello M. The effect of genetic education on the referral of patients to genetic evaluation: Findings from a national survey of nephrologists. Genet. Med. 2023;25:100814. doi: 10.1016/j.gim.2023.100814. PubMed DOI PMC

Mrug M., Bloom M.S., Seto C., Malhotra M., Tabriziani H., Gauthier P., Sidlow V., McKanna T., Billings P.R. Genetic Testing for Chronic Kidney Diseases: Clinical Utility and Barriers Perceived by Nephrologists. Kidney Med. 2021;3:1050–1056. doi: 10.1016/j.xkme.2021.08.006. PubMed DOI PMC

Dvela-Levitt M., Kost-Alimova M., Emani M., Kohnert E., Thompson R., Sidhom E.-H., Rivadeneira A., Sahakian N., Roignot J., Papagregoriou G., et al. Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy. Cell. 2019;178:521–535.e23. doi: 10.1016/j.cell.2019.07.002. PubMed DOI

Jayasinghe K., Quinlan C., Mallett A.J., Kerr P.G., McClaren B., Nisselle A., Mallawaarachchi A., Polkinghorne K.R., Patel C., Best S., et al. Attitudes and Practices of Australian Nephrologists Toward Implementation of Clinical Genomics. Kidney Int. Rep. 2021;6:272–283. doi: 10.1016/j.ekir.2020.10.030. PubMed DOI PMC

Connaughton D.M., Kennedy C., Shril S., Mann N., Murray S.L., Williams P.A., Conlon E., Nakayama M., van der Ven A.T., Ityel H., et al. Monogenic causes of chronic kidney disease in adults. Kidney Int. 2019;95:914–928. doi: 10.1016/j.kint.2018.10.031. PubMed DOI PMC

Lata S., Marasa M., Li Y., Fasel D.A., Groopman E., Jobanputra V., Rasouly H., Mitrotti A., Westland R., Verbitsky M., et al. Whole-Exome Sequencing in Adults With Chronic Kidney Disease A Pilot Study. Ann. Intern. Med. 2018;168:100–109. doi: 10.7326/M17-1319. PubMed DOI PMC

Braun D.A., Schueler M., Halbritter J., Gee H.Y., Porath J.D., Lawson J.A., Airik R., Shril S., Allen S.J., Stein D., et al. Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. Kidney Int. 2016;89:468–475. doi: 10.1038/ki.2015.317. PubMed DOI PMC

Burnes D., Sheppard C., Henderson C.R., Wassel M., Cope R., Barber C., Pillemer K. Interventions to Reduce Ageism Against Older Adults: A Systematic Review and Meta-Analysis. Am. J. Public Health. 2019;109:e1–e9. doi: 10.2105/AJPH.2019.305123. PubMed DOI PMC

Beal F., Forrester N., Watson E., Williams M., Buckton A., Marlais M., Maxted A., UK Gene Panel Study Group. Woolf A.S., Saleem M.A., et al. A targeted gene panel illuminates pathogenesis in young people with unexplained kidney failure. J. Nephrol. 2024;37:1273–1284. doi: 10.1007/s40620-024-01964-1. PubMed DOI

Knoers N., Antignac C., Bergmann C., Dahan K., Giglio S., Heidet L., Lipska-Ziętkiewicz B.S., Noris M., Remuzzi G., Vargas-Poussou R., et al. Genetic testing in the diagnosis of chronic kidney disease: Recommendations for clinical practice. Nephrol. Dial. Transplant. 2022;37:239–254. doi: 10.1093/ndt/gfab218. PubMed DOI PMC

Bleyer A.J., Kmoch S., Antignac C., Robins V., Kidd K., Kelsoe J.R., Hladik G., Klemmer P., Knohl S.J., Scheinman S.J., et al. Variable clinical presentation of an MUC1 mutation causing medullary cystic kidney disease type 1. Clin. J. Am. Soc. Nephrol. 2014;9:527–535. doi: 10.2215/CJN.06380613. PubMed DOI PMC

Dusic E.J., Theoryn T., Wang C., Swisher E.M., Bowen D.J. Barriers, interventions, and recommendations: Improving the genetic testing landscape. Front. Digit. Health. 2022;4:961128. doi: 10.3389/fdgth.2022.961128. PubMed DOI PMC

Schott C., Dilliott A.A., Wang J., McIntyre A.D., Son S., Colaiacovo S., Baker C., Gunaratnam L., House A.A., Huang S.-H.S., et al. Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6. Gene. 2024;927:148731. PubMed

Schott C., Colaiacovo S., Baker C., Weir M.A., Connaughton D.M. Reclassification of Genetic Testing Results: A Case Report Demonstrating the Need for Structured Re-Evaluation of Genetic Findings. Can. J. Kidney Health Dis. 2024;11:20543581241242562. doi: 10.1177/20543581241242562. PubMed DOI PMC