biostudies-literatureMilo Rasouly HNIDDK NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)7290https://www.ebi.ac.uk/biostudies/studies/S-EPMC12332173biostudies-literatureUnknown16(1)Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.1% of cases. We find a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of CAKUT patients with diagnostic variants have neurodevelopmental or cardiac phenotypes. We identify 40 candidate genes, including CELSR1, SSBP2, XPO1, NR6A1, and ARID3A. Two are confirmed as CAKUT geNature communicationsExome analysis links kidney malformations to developmental disorders and reveals causal genes.PMC12332173R01 DK115574P20 DK1161915K01DK1324955R01DK080099-13R56 DK1381645U54DK104309-101S10OD030363-01A1R01 DK103184Martino JKe JHays TKil BHKisselev STondolo FMasnata GMontini GJin GKiryluk KBiancone LReytan-Miron SAlam SRanghino ALa Manna GMu XMorban MShril SLekkerkerker ILatos-Bielenska AMane SZamboli PCapone VPiva SLin FBorszewska-Kornacka MKFiaccadori EBheda SMarzuillo PGliwinska AUy NSWongboonsin JMaterna-Kiryluk AMizerska-Wasiak MTkaczyk MSzmigielska AMarasa MZhang JYAppel GBLozanovski VJBradbury DCaliskan YGharavi AGPisani ISaraga MSantoro DIonita-Laza IElefant NTomar Nvan Eerde AMAmoroso AGrandinetti VDrozdz DZaza GKrishna Murthy SBLifton RPCohen DJBodria MHarnof OHildebrandt FMeneghesso DLugani FBadenski AKrzemien GLa Scola CChatterjee DSanna-Cherchi SGoldstein DZachwieja KGuarino SLim TYBomback ASMiklaszewska MRadhakrishnan JStevens KOWestland RReingold RSikora PKolupaeva VBeenken AZaniew MBjanid OCrew RJCanetta PAYang SScolari FPovysil GGroopman EETasic VMehl KVerbitsky MNegrisolo SRao MKMilo Rasouly HMittrori AZheng JEsposito PIzzi CGhavami IGesualdo LKhan ASzczepanska MGhiggeri GMVena NBaraldi OCoughlin ACFasel DJamry-Dziurla AfalseExome analysis links kidney malformations to developmental disorders and reveals causal genes.Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.1% of cases. We find a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of CAKUT patients with diagnostic variants have neurodevelopmental or cardiac phenotypes. We identify 40 candidate genes, including CELSR1, SSBP2, XPO1, NR6A1, and ARID3A. Two are confirmed as CAKUT ge2025-01-01T00:00:00Z2025 Aug2026-05-01T08:39:24.19Z2026-04-19T03:07:59.971ZS-EPMC123321734077495810.1038/s41467-025-62319-3