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.
Nature genetics. 2018 Dec 21 [Epub]
Miguel Verbitsky, Rik Westland, Alejandra Perez, Krzysztof Kiryluk, Qingxue Liu, Priya Krithivasan, Adele Mitrotti, David A Fasel, Ekaterina Batourina, Matthew G Sampson, Monica Bodria, Max Werth, Charlly Kao, Jeremiah Martino, Valentina P Capone, Asaf Vivante, Shirlee Shril, Byum Hee Kil, Maddalena Marasà, Jun Y Zhang, Young-Ji Na, Tze Y Lim, Dina Ahram, Patricia L Weng, Erin L Heinzen, Alba Carrea, Giorgio Piaggio, Loreto Gesualdo, Valeria Manca, Giuseppe Masnata, Maddalena Gigante, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E van Wijk, Marijan Saraga, Domenico Santoro, Giovanni Conti, Pasquale Zamboli, Hope White, Dorota Drozdz, Katarzyna Zachwieja, Monika Miklaszewska, Marcin Tkaczyk, Daria Tomczyk, Anna Krakowska, Przemyslaw Sikora, Tomasz Jarmoliński, Maria K Borszewska-Kornacka, Robert Pawluch, Maria Szczepanska, Piotr Adamczyk, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, Mark G Dobson, John M Darlow, Prem Puri, David E Barton, Susan L Furth, Bradley A Warady, Zoran Gucev, Vladimir J Lozanovski, Velibor Tasic, Isabella Pisani, Landino Allegri, Lida M Rodas, Josep M Campistol, Cécile Jeanpierre, Shumyle Alam, Pasquale Casale, Craig S Wong, Fangming Lin, Débora M Miranda, Eduardo A Oliveira, Ana Cristina Simões-E-Silva, Jonathan M Barasch, Brynn Levy, Nan Wu, Friedhelm Hildebrandt, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna-Kiryluk, Feng Zhang, Hakon Hakonarson, Virginia E Papaioannou, Cathy L Mendelsohn, Ali G Gharavi, Simone Sanna-Cherchi
Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA., Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA., University of Michigan School of Medicine, Department of Pediatrics-Nephrology, Ann Arbor, MI, USA., Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy., Center for Applied Genomics, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Department of Pediatric Nephrology, UCLA Medical Center and UCLA Medical Center-Santa Monica, Los Angeles, CA, USA., Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA., Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Department of Pediatric Urology, Azienda Ospedaliera Brotzu, Cagliari, Italy., National Research Council of Italy, Inst. 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Martino", Messina, Italy., Division of Nephrology, University of Campania "Luigi Vanvitell", Naples, Italy., Department of Pediatric Nephrology and Hypertension, Dialysis Unit, Jagiellonian University Medical College, Krakow, Poland., Department of Pediatric Nephrology, Jagiellonian University Medical College, Krakow, Poland., Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland., Department of Pediatric Nephrology Medical University of Lublin, Lublin, Poland., Children's Department, Międzyrzecki Hospital, Międzyrzecz, Poland., Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland., Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland., Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland., Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland., National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland., Departments of Pediatrics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Division of Nephrology, Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA., Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Division of Nephrology, Children's Mercy Kansas City, Kansas City, MO, USA., University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia., Department of Medicine and Surgery, University of Parma, Parma, Italy., ICNU-Nephrology and Urology Department, Barcelona, Spain., Laboratory of Hereditary Kidney Diseases, Inserm UMR 1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Department of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA., Division of Pediatric Nephrology, University of New Mexico Children's Hospital, Albuquerque, NM, USA., Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, NY, USA., Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil., Department of Pathology and Cell Biology, Columbia University, New York, NY, USA., Department of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Medical Research Center of Orthopedics, all at Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China., Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland., Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China., Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA. ., Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA. ., Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA. ., Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA. .