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

Authors

Miguel Verbitsky, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Rik Westland, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA; Department of Pediatric Nephrology, Amsterdam UMC, Amsterdam, the Netherlands
Alejandra Perez, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Krzysztof Kiryluk, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Qingxue Liu, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Priya Krithivasan, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Adele Mitrotti, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
David A Fasel, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Ekaterina Batourina, Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Matthew G. Sampson, University of Michigan School of Medicine, Department of Pediatrics-Nephrology, Ann Arbor, MI, USA
Monica Bodria, Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy
Max Werth, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Charlly Kao, Center for Applied Genomics, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Jeremiah Martino, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Valentina P Capone, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Asaf Vivante, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Pediatric Department B and Pediatric Nephrology Unit, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Shirlee Shril, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Byum Hee Kil, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Maddalena Marasà, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Jun Y. Zhang, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Young-Ji Na, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Tze Y. Lim, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Dina Ahram, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Patricia L. Weng, Department of Pediatric Nephrology, UCLA Medical Center and UCLA Medical Center-Santa Monica, Los Angeles, CA, USA
Erin L. Heinzen, Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA
Alba Carrea, Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy
Giorgio Piaggio, Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy
Loreto Gesualdo, Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
Valeria Manca, Department of Pediatric Urology, Azienda Ospedaliera Brotzu, Cagliari, Italy
Giuseppe Masnata, Department of Pediatric Urology, Azienda Ospedaliera Brotzu, Cagliari, Italy
Maddalena Gigante, Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
Daniele Cusi, National Research Council of Italy, Inst. Biomedical Technologies Milano Bio4dreams Scientific Unit, Milano, Italy
Claudia Izzi, Dipartimento Ostetrico-Ginecologico e Seconda Divisione di Nefrologia ASST, Spedali Civili e Presidio di Montichiari, Brescia, Italy
Francesco Scolari, Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia, Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia, Italy
Joanna A E van Wijk, Department of Pediatric Nephrology, Amsterdam UMC, Amsterdam, the Netherlands
Marijan Saraga, Department of Pediatrics, University Hospital of Split, Split, Croatia; School of Medicine, University of Split, Split, Croatia
Domenico Santoro, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Messina, Messina, Italy
Giovanni Conti, Department of Pediatric Nephrology, Azienda Ospedaliera Universitaria "G. Martino", Messina, Italy
Pasquale Zamboli, Division of Nephrology, University of Campania "Luigi Vanvitell", Naples, Italy
Hope White, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Dorota Drozdz, Department of Pediatric Nephrology and Hypertension, Dialysis Unit, Jagiellonian University Medical College, Krakow, Poland
Katarzyna Zachwieja, Department of Pediatric Nephrology and Hypertension, Dialysis Unit, Jagiellonian University Medical College, Krakow, Poland
Monika Miklaszewska, Department of Pediatric Nephrology, Jagiellonian University Medical College, Krakow, Poland
Marcin Tkaczyk, Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
Daria Tomczyk, Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
Anna Krakowska, Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
Przemyslaw Sikora, Department of Pediatric Nephrology Medical University of Lublin, Lublin, Poland
Tomasz Jarmoliński, Children's Department, Międzyrzecki Hospital, Międzyrzecz, Poland
Maria K. Borszewska-Kornacka, Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
Robert Pawluch, Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
Maria Szczepanska, Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
Piotr Adamczyk, Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
Malgorzata Mizerska-Wasiak, Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
Grazyna Krzemien, Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
Agnieszka Szmigielska, Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
Marcin Zaniew, Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland
Mark G. Dobson, 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
John M. Darlow, 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
Prem Puri, National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; National Children's Hospital Tallaght, Dublin, Ireland
David E. Barton, Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; University College Dublin UCD School of Medicine, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
Susan L. Furth, 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
Bradley A. Warady, Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Division of Nephrology, Children's Mercy Kansas City, Kansas City, MO, USA
Zoran Gucev, University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia
Vladimir J. Lozanovski, University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia; University Clinic for General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
Velibor Tasic, University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia
Isabella Pisani, Department of Medicine and Surgery, University of Parma, Parma, Italy
Landino Allegri, Department of Medicine and Surgery, University of Parma, Parma, Italy
Lida M. Rodas, Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Josep M. Campistol, Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Cécile Jeanpierre, Laboratory of Hereditary Kidney Diseases, Inserm UMR 1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France
Shumyle Alam, Department of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Pasquale Casale, Department of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA; Mount Sinai Medical Center, Kravis Children's Hospital, New York, NY, USA
Craig S. Wong, Division of Pediatric Nephrology, University of New Mexico Children's Hospital, Albuquerque, NM, USA
Fangming Lin, Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, NY, USA
Débora M. Miranda, Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
Eduardo A. Oliveira, Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
Ana Cristina Simões-E-Silva, Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
Jonathan M. Barasch, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Brynn Levy, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
Nan Wu, 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 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Friedhelm Hildebrandt, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Gian Marco Ghiggeri, Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy
Anna Latos-Bielenska, Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland
Anna Materna-Kiryluk, Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland
Feng Zhang, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Hakon Hakonarson, Center for Applied Genomics, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Virginia E. Papaioannou, Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
Cathy L. Mendelsohn, Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Ali G. Gharavi, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
Simone Sanna-Cherchi, Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA

Document Type

Article

Publication Date

1-1-2019

Abstract

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.

Publisher

Nature Pub. Co.

Publication Title

Nature genetics

ISSN

1546-1718

Volume

51

Issue

1

First Page

117

Last Page

127

DOI

10.1038/s41588-018-0281-y

Recommended Citation

Verbitsky M, Westland R, Perez A, Kiryluk K, Liu Q, Krithivasan P, Mitrotti A, Fasel DA, Batourina E, Sampson MG, Bodria M, Werth M, Kao C, Martino J, Capone VP, Vivante A, Shril S, Kil BH, Marasà M, Zhang JY, Na YJ, Lim TY, Ahram D, Weng PL, Heinzen EL, Carrea A, Piaggio G, Gesualdo L, Manca V, Masnata G, Gigante M, Cusi D, Izzi C, Scolari F, van Wijk JAE, Saraga M, Santoro D, Conti G, Zamboli P, White H, Drozdz D, Zachwieja K, Miklaszewska M, Tkaczyk M, Tomczyk D, Krakowska A, Sikora P, Jarmoliński T, Borszewska-Kornacka MK, Pawluch R, Szczepanska M, Adamczyk P, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Dobson MG, Darlow JM, Puri P, Barton DE, Furth SL, Warady BA, Gucev Z, Lozanovski VJ, Tasic V, Pisani I, Allegri L, Rodas LM, Campistol JM, Jeanpierre C, Alam S, Casale P, Wong CS, Lin F, Miranda DM, Oliveira EA, Simões-E-Silva AC, Barasch JM, Levy B, Wu N, Hildebrandt F, Ghiggeri GM, Latos-Bielenska A, Materna-Kiryluk A, Zhang F, Hakonarson H, Papaioannou VE, Mendelsohn CL, Gharavi AG, Sanna-Cherchi S. The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nat Genet. 2019 Jan;51(1):117-127. doi: 10.1038/s41588-018-0281-y. Epub 2018 Dec 21. Erratum in: Nat Genet. 2019 Apr;51(4):764. PMID: 30578417; PMCID: PMC6668343.