{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:55:50Z","timestamp":1781585750140,"version":"3.54.5"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are among the most common congenital malformations and the leading cause of chronic kidney disease in children. They arise when key steps in kidney development are disrupted, including ureteric bud induction, branching morphogenesis and nephron progenitor differentiation. These processes depend on coordinated transcriptional programs, signaling pathways, ciliary function and proper extracellular matrix (ECM) organization. Advances in whole exome and whole genome sequencing, as well as copy number variation analysis, have expanded the spectrum of known monogenic causes. Pathogenic variants have now been identified in major transcriptional regulators and multiple ciliopathy-related genes. Evidence also points to defects in central signaling pathways and changes in ECM composition as contributors to CAKUT pathogenesis. Clinical presentations vary widely, shaped by modifying effects of genetic background, epigenetic regulation and environmental influences such as maternal diabetes and fetal hypoxia. Emerging tools, including human kidney organoids, gene-editing approaches and single-cell or spatial transcriptomics, allow detailed exploration of developmental mechanisms and validation of candidate pathways. Overall, CAKUT reflects a multifactorial condition shaped by interacting genetic, epigenetic and environmental determinants. Integrating genomic data with experimental models is essential for improving diagnosis, deepening biological insight and supporting the development of targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms27010017","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:03:46Z","timestamp":1766142226000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["From Genes to Malformations: Molecular Mechanisms Driving the Pathogenesis of Congenital Anomalies of the Kidney and Urinary Tract"],"prefix":"10.3390","volume":"27","author":[{"given":"Maria","family":"Fourikou","sequence":"first","affiliation":[{"name":"Third Department of Pediatrics, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5217-1766","authenticated-orcid":false,"given":"John","family":"Dotis","sequence":"additional","affiliation":[{"name":"Third Department of Pediatrics, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"723","DOI":"10.2215\/CJN.12581019","article-title":"A Primer on Congenital Anomalies of the Kidneys and Urinary Tracts (CAKUT)","volume":"15","author":"Murugapoopathy","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Botero-Calderon, L., Lawrence, A., O\u2019Toole, N., and Guay-Woodford, L.M. (2023). Fetal renal cystic disease and post-natal follow up-a single center experience. Front. Pediatr., 11.","DOI":"10.3389\/fped.2023.1243504"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mahmoud, A.H., Talaat, I.M., Tlili, A., and Hamoudi, R. (2024). Congenital anomalies of the kidney and urinary tract. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1384676"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Brockwell, M., Hergenrother, S., Satariano, M., Shah, R., and Raina, R. (2024). Pathophysiology of Congenital Anomalies of the Kidney and Urinary Tract: A Comprehensive Review. Cells, 13.","DOI":"10.3390\/cells13221866"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41581-025-00951-4","article-title":"Ureter development and associated congenital anomalies","volume":"21","author":"Kispert","year":"2025","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40348-021-00112-0","article-title":"Molecular causes of congenital anomalies of the kidney and urinary tract (CAKUT)","volume":"8","author":"Kohl","year":"2021","journal-title":"Mol. Cell Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.scib.2024.01.035","article-title":"Progress and clinical prospect of genomic structural variants investigation","volume":"69","author":"Chen","year":"2024","journal-title":"Sci. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41431-024-01710-y","article-title":"Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract","volume":"33","author":"Kesdiren","year":"2025","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Merz, L.M., Shril, S., Carrocci, T.J., Rezi, C.K., Zeps, N.J., Jim\u00e9nez-Izquierdo, R., Bergmann, F., Petriman, N.A., Kolvenbach, C.M., and Mertens, N.D. (2025). CAKUT variants in PRPF8, DYRK2, and CEP78: Implications for splicing and ciliogenesis. bioRxiv, bioRxiv:2025.07.16.665151.","DOI":"10.1101\/2025.07.16.665151"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.kint.2023.11.032","article-title":"Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)","volume":"105","author":"Riedhammer","year":"2024","journal-title":"Kidney Int."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Cazorla, E., Carrera, N., and Garc\u00eda-Gonz\u00e1lez, M.\u00c1. (2024). HNF1B Transcription Factor: Key Regulator in Renal Physiology and Pathogenesis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910609"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1152\/physiolgenomics.00112.2019","article-title":"Whole genome sequencing and novel candidate genes for CAKUT and altered nephrogenesis in the HSRA rat","volume":"52","author":"Showmaker","year":"2020","journal-title":"Physiol. Genom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7290","DOI":"10.1038\/s41467-025-62319-3","article-title":"Exome analysis links kidney malformations to developmental disorders and reveals causal genes","volume":"16","author":"Vena","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1038\/s41431-025-01929-3","article-title":"Clinical exome sequencing efficacy and phenotypic expansions involving non-isolated congenital anomalies of kidney and urinary tract (CAKUT+)","volume":"33","author":"Zhao","year":"2025","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/s41581-023-00742-9","article-title":"The genetics and pathogenesis of CAKUT","volume":"19","author":"Kolvenbach","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"395","DOI":"10.12688\/f1000research.51018.1","article-title":"Overlap of vitamin A and vitamin D target genes with CAKUT-related processes","volume":"10","author":"Ozisik","year":"2021","journal-title":"F1000Research"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17746","DOI":"10.1038\/s41598-022-22749-1","article-title":"Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT","volume":"12","author":"Mitrovic","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1007\/s00467-024-06381-x","article-title":"Copy number variation analysis identifies MIR9-3 and MIR1299 as novel miRNA candidate genes for CAKUT","volume":"39","author":"Zivotic","year":"2024","journal-title":"Pediatr. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20731","DOI":"10.1038\/s41598-024-71721-8","article-title":"Integrative analysis of multi-omics data reveals importance of collagen and the PI3K AKT signalling pathway in CAKUT","volume":"14","author":"Bayjanov","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kelam, N., Ogorevc, M., Gotovac, I., Kuzmi\u0107 Prusac, I., Vukojevi\u0107, K., Saraga-Babi\u0107, M., and Marde\u0161i\u0107, S. (2025). Analysis of Kallikrein 6, Acetyl-\u03b1-Tubulin, and Aquaporin 1 and 2 Expression Patterns During Normal Human Nephrogenesis and in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Genes, 16.","DOI":"10.3390\/genes16050499"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00467-024-06479-2","article-title":"Translational strategies to uncover the etiology of congenital anomalies of the kidney and urinary tract","volume":"40","author":"Vendrig","year":"2025","journal-title":"Pediatr. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1038\/ki.2015.239","article-title":"Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney","volume":"88","author":"Westland","year":"2015","journal-title":"Kidney Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1111\/cge.14615","article-title":"Genetics of anomalies of the kidney and urinary tract with congenital heart disease: A review","volume":"106","author":"Barakat","year":"2024","journal-title":"Clin. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Leskur, M., Leskur, D., Marijan, S., Minarik, L., and Lozi\u0107, B. (2025). Congenital Anomalies of the Kidney and Urinary Tract in Down Syndrome: Prevalence, Phenotypes, Genetics and Clinical Management. Genes, 16.","DOI":"10.3390\/genes16030245"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Capone, V.P., Morello, W., Taroni, F., and Montini, G. (2017). Genetics of Congenital Anomalies of the Kidney and Urinary Tract: The Current State of Play. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040796"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s40246-024-00606-8","article-title":"GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract","volume":"18","author":"Du","year":"2024","journal-title":"Hum. Genom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/s41431-023-01331-x","article-title":"Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): A single-center experience","volume":"31","author":"Riedhammer","year":"2023","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/cge.14406","article-title":"A novel homozygous missense variant in TBC1D31 in a consanguineous family with congenital anomalies of the kidney and urinary tract (CAKUT)","volume":"104","author":"Kalyoncu","year":"2023","journal-title":"Clin. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.gim.2021.09.010","article-title":"Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT","volume":"24","author":"Seltzsam","year":"2022","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/pd.5536","article-title":"Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT)","volume":"39","author":"Talati","year":"2019","journal-title":"Prenat. Diagn."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1681\/ASN.2017121265","article-title":"Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract","volume":"29","author":"Connaughton","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Velja\u010di\u0107 Viskovi\u0107, D., Lozi\u0107, M., Vukoja, M., \u0160olji\u0107, V., Vukojevi\u0107, K., Glavina Durdov, M., Filipovi\u0107, N., and Lozi\u0107, B. (2023). Spatio-Temporal Expression Pattern of CAKUT Candidate Genes DLG1 and KIF12 during Human Kidney Development. Biomolecules, 13.","DOI":"10.3390\/biom13020340"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41390-024-03178-4","article-title":"Genetic analysis of congenital unilateral renal agenesis in children based on next-generation sequencing","volume":"97","author":"Yang","year":"2025","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1093\/ndt\/gfab253","article-title":"Whole-exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract","volume":"37","author":"Zheng","year":"2022","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhou, J.X., and Li, X. (2021). Non-Coding RNAs in Hereditary Kidney Disorders. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063014"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/ki.2015.319","article-title":"Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT","volume":"89","author":"Nicolaou","year":"2016","journal-title":"Kidney Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s12519-021-00428-x","article-title":"Responsible genes in children with primary vesicoureteral reflux: Findings from the Chinese Children Genetic Kidney Disease Database","volume":"17","author":"Liu","year":"2021","journal-title":"World J. Pediatr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1016\/j.kint.2019.01.025","article-title":"SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes","volume":"95","author":"Kim","year":"2019","journal-title":"Kidney Int."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Harris, M., Schuh, M.P., McKinney, D., Kaufman, K., and Erkan, E. (2022). Whole Exome Sequencing in a Population With Severe Congenital Anomalies of Kidney and Urinary Tract. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.898773"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1016\/j.ekir.2023.08.008","article-title":"Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life","volume":"8","author":"Werfel","year":"2023","journal-title":"Kidney Int. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.1016\/j.ekir.2025.07.011","article-title":"Exome Sequencing in Saudi Arabian Pediatric Kidney Disease Single-Center Cohort","volume":"10","author":"Lemberg","year":"2025","journal-title":"Kidney Int. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101432","DOI":"10.1016\/j.gim.2025.101432","article-title":"Trio exome sequencing identifies de novo variants in novel candidate genes in 19.62% of CAKUT families","volume":"27","author":"Merz","year":"2025","journal-title":"Genet. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/17\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:06:42Z","timestamp":1766142402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010017"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010017","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,19]]}}}