The copy number variation landscape of congenital anomalies of the kidney and urinary tract

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Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

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Fig. 1: Burden of rare copy number variants in CAKUT cases compared with controls.
Fig. 2: Common genomic disorders loci in CAKUT cases and their prevalence in controls.
Fig. 3: Analysis of urinary tract phenotypes in Tbx6rv/– mutants.
Fig. 4: Analysis of urinary tract phenotypes in Tbx6rv/rv mutants.

Data availability

Raw data that support the findings of this study will in part be available from the corresponding authors upon reasonable request and are in part available from dbGaP (; accession pending). Some restrictions may apply according to participants’ consent and privacy protection. All images generated from mouse experiments reported in this study will also be available from the corresponding authors upon reasonable request.


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We thank all patients and family members for participating in this study. We thank J. R. Lupski for critical review of this manuscript. This work was supported by grants (1R01DK103184, 1R21DK098531 and UL1 TR000040, to S.S.-C.; 2R01DK080099, to A.G.G.; 3U54DK104309, to A.G.G., C.L.M. and J.M.B.; R37HD033082, to V.E.P.; and 1R01DK105124 to K.K.) from the National Institutes of Health (NIH); a grant-in-aid (13GRNT14680075, to S.S.-C.) from the American Heart Association; a grant (RF-2010–2307403, to S.S.-C. and G.M.G.) from the Joint Italian Ministry of Health and NIH Young Investigators Finalized Research; a grant (to G.M.G.) from the Fondazione Malattie Renali nel Bambino; grants to D.E.B. and P.P. from the National Children’s Research Centre and the Irish Health Research Board (HRA-POR-2014–693); a grant (AAE07007KSA, to C.J.) from the GIS-Institut des Maladies Rares; by the Polish Ministry of Health (to A.M.K. and A.L.-B.); by the Polish Kidney Genetics Network (POLYGENES), the Polish Registry of Congenital Malformations (PRCM) and the NZOZ Center for Medical Genetics (GENESIS); by grants (to the Chronic Kidney Disease in Children Study) from the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; by grants (U01DK66143, U01DK66174, U01DK082194, U01DK66116 and RO1DK082394) from the National Heart, Lung, and Blood Institute; and by the Paul Marks Scholar Award (to S.S.-C.); CNPq grant 460334/2014-0 and FAPEMIG grant PPM-005555-15 (to D.M.M., E.A.O. and A.C.S.-e.-S.); and a Kolff Postdoc Fellowship Abroad grant (15OKK95, to R.W.) from the Dutch Kidney Foundation. S.S.-C. is supported as the Florence Irving Assistant Professor of Medicine at Columbia University. We thank D.B. Goldstein for providing infrastructure for whole-exome sequencing at the Institute for Genomic Medicine (IGM) at Columbia University, and for critical review of the manuscript. Acknowledgments to the investigators who contributed of whole-exome sequencing data for 15,469 controls from the IGM warehouse can be found in the Supplementary Note.

Author information

S.S.-C. directed the project. V.E.P., C.L.M., A.G.G. and S.S.-C. designed the project. M.V., R.W., A.P., Q.L., P.K., D.A.F., E.B., M.W., J.M., V.P.C., Y.-J.N., T.Y.L., D.A. and H.W. performed the experiments and/or data generation. M.G.S., M.G.D., J.M.D., P.P., D.E.B., S.L.F., B.A.W., C.J., D.M.M., E.A.O., A.C.S.-e.-S., F.H. and H.H. contributed array genotype data for CNV analyses. M.V., R.W., P.K., A.P., E.B., A.M., V.E.P., C.L.M. and S.S.-C. analyzed the data. K.K., J.M.B. and B.L. provided critical intellectual content for the design of the study. All other authors (A.M., M.B., C.K., A.V., S.S., B.H.K., M.M., J.Y.Z., P.L.W., E.L.H., A.C., G.P., L.G., V.M., G.M., M.G., D.C., C.I., F.S., J.A.E.v.W., M. Saraga, D.S., G.C., P.Z., D.D., K.Z., M.M., M.T., D.T., A.K., P.S., T.J., M.K.B.-K., R.P., M. Szczepanska., P.A., M.M.-W., G.K., A.S., M.Z., Z.G., V.J.L., V.T., I.P., L.A., L.M.R., J.M.C., S.A., P.C., F.L., W.N., G.M.G., A.L.-B., A.M.-K., C.S.W., N.W. and F.Z.) recruited cases and submitted clinical information for the study. M.V., R.W., V.E.P., C.L.M., A.G.G. and S.S.-C. wrote the draft of the manuscript. All authors critically revised the manuscript.

Correspondence to Virginia E. Papaioannou or Cathy L. Mendelsohn or Ali G. Gharavi or Simone Sanna-Cherchi.

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