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

      research-article
      1 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 4 , 5 , 1 , 6 , 1 , 1 , 7 , 8 , 7 , 1 , 1 , 1 , 1 , 1 , 1 , 9 , 10 , 5 , 5 , 11 , 12 , 12 , 11 , 13 , 14 , 15 , 2 , 16 , 17 , 18 , 19 , 20 , 1 , 21 , 21 , 22 , 23 , 23 , 23 , 24 , 25 , 26 , 26 , 26 , 26 , 27 , 27 , 27 , 28 , 29 , 30 , 29 , 30 , 30 , 31 , 29 , 32 , 33 , 34 , 35 , 35 , 36 , 35 , 37 , 37 , 38 , 38 , 39 , 40 , 40 , 41 , 42 , 43 , 44 , 44 , 44 , 1 , 45 , 46 , 47 , 7 , 5 , 48 , 48 , 49 , 6 , 50 , $ , 3 , $ , 1 , $ , 1 , $
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          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 (i.e. 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; 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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          Most cited references69

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          Large recurrent microdeletions associated with schizophrenia.

          Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
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            • Record: found
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            Is Open Access

            The ExAC browser: displaying reference data information from over 60 000 exomes

            Worldwide, hundreds of thousands of humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation and understanding gene function. Here, we present a lightweight, flexible browser framework to display large population datasets of genetic variation. We demonstrate its use for exome sequence data from 60 706 individuals in the Exome Aggregation Consortium (ExAC). The ExAC browser provides gene- and transcript-centric displays of variation, a critical view for clinical applications. Additionally, we provide a variant display, which includes population frequency and functional annotation data as well as short read support for the called variant. This browser is open-source, freely available at http://exac.broadinstitute.org, and has already been used extensively by clinical laboratories worldwide.
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              • Record: found
              • Abstract: found
              • Article: not found

              Mechanisms underlying structural variant formation in genomic disorders.

              With the recent burst of technological developments in genomics, and the clinical implementation of genome-wide assays, our understanding of the molecular basis of genomic disorders, specifically the contribution of structural variation to disease burden, is evolving quickly. Ongoing studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based processes and in replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and also highlight the tremendous plasticity and dynamic nature of our genome in evolution, health and disease susceptibility.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                26 July 2019
                21 December 2018
                January 2019
                31 July 2019
                : 51
                : 1
                : 117-127
                Affiliations
                [1 ]Division of Nephrology, Department of Medicine, Columbia University, New York, New York, USA.
                [2 ]Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
                [3 ]Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
                [4 ]University of Michigan School of Medicine, Department of Pediatrics-Nephrology, Ann Arbor, Michigan, USA.
                [5 ]Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy.
                [6 ]Center for Applied Genomics, The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
                [7 ]Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
                [8 ]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.
                [9 ]Department of Pediatric Nephrology, UCLA Medical Center and UCLA Medical Center-Santa Monica, Los Angeles, California, USA.
                [10 ]Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, USA.
                [11 ]Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
                [12 ]Department of Pediatric Urology, Azienda Ospedaliera Brotzu, Cagliari, Italy.
                [13 ]National Research Council of Italy, Inst. Biomedical Technologies Milano Bio4dreams Scientific Unit, Milano, Italy.
                [14 ]Dipartimento Ostetrico-Ginecologico e Seconda Divisione di Nefrologia ASST, Spedali Civili e Presidio di Montichiari, Brescia, Italy.
                [15 ]Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia, Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia, Italy.
                [16 ]Department of Pediatrics, University Hospital of Split, Split, Croatia.
                [17 ]School of Medicine, University of Split, 21000, Split, Croatia.
                [18 ]Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Messina, Messina, Italy.
                [19 ]Department of Pediatric Nephrology, Azienda Ospedaliera Universitaria “G. Martino”, Messina, Italy.
                [20 ]Division of Nephrology, University of Campania “Luigi Vanvitelli”, Naples, Italy.
                [21 ]Department of Pediatric Nephrology and Hypertension, Dialysis Unit, Jagiellonian University Medical College, Krakow, Poland
                [22 ]Department of Pediatric Nephrology, Jagiellonian University Medical College, Krakow, Poland.
                [23 ]Department of Pediatrics, Immunology and Nephrology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland.
                [24 ]Department of Pediatric Nephrology Medical University of Lublin, Lublin, Poland.
                [25 ]Children’s Department, Międzyrzecki Hospital, Międzyrzecz, Poland
                [26 ]Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Poland.
                [27 ]Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.
                [28 ]Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland.
                [29 ]Department of Clinical Genetics, Our Lady’s Children’s Hospital Crumlin, Dublin, 12, Ireland
                [30 ]National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, 12, Ireland.
                [31 ]National Children’s Hospital Tallaght, Dublin, 24, Ireland.
                [32 ]University College Dublin UCD School of Medicine, Our Lady’s Children’s Hospital Crumlin, Dublin, 12, Ireland.
                [33 ]Departments of Pediatrics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Division of Nephrology, Children’s Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.
                [34 ]Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Division of Nephrology, Children’s Mercy Kansas City, Kansas City, Missouri, USA
                [35 ]University Children’s Hospital, Medical Faculty of Skopje, Skopje, Macedonia.
                [36 ]University Clinic for General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany
                [37 ]Department of Medicine and Surgery, University of Parma, Italy.
                [38 ]ICNU-Nephrology and Urology Department, Barcelona, Spain.
                [39 ]Laboratory of Hereditary Kidney Diseases, Inserm UMR 1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
                [40 ]Department of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
                [41 ]Mount Sinai Medical Center, Kravis Children’s Hospital, New York, New York, USA.
                [42 ]Division of Pediatric Nephrology, University of New Mexico Children’s Hospital, Albuquerque, New Mexico, USA.
                [43 ]Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, New York, USA.
                [44 ]Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil.
                [45 ]Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
                [46 ]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.
                [47 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
                [48 ]Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.
                [49 ]Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
                [50 ]Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.
                Author notes
                [*]

                Both authors contributed equally to this work.

                [$ ]To whom correspondence should be addressed, Simone Sanna-Cherchi, M.D., Division of Nephrology, Columbia University College of Physicians and Surgeons, 1150 Street Nicholas Avenue, Russ Berrie Pavilion #412D, New York, New York 10032, USA. ss2517@ 123456cumc.columbia.edu ., Ali G. Gharavi, M.D., Division of Nephrology, Columbia University College of Physicians and Surgeons, 1150 Street Nicholas Avenue, Russ Berrie Pavilion #412C, New York, New York 10032, USA. ag2239@ 123456cumc.columbia.edu ., Cathy L. Mendelsohn, Ph.D., Department of Urology, Columbia University College of Physicians and Surgeons, 1130 Street Nicholas Avenue, IRCC #311, New York, New York 10032, USA. clm20@ 123456cumc.columbia.edu ., Virginia E. Papaioannou, Ph.D., Department of Genetics and Development, Columbia University Medical Center, 701 W 168th Street, HHSC #1602, New York, New York, 10032, USA. vep1@ 123456cumc.columbia.edu

                AUTHOR CONTRIBUTIONS

                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.N., T.L., D.A., 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 to the design of the study. All other authors (A.M., M.B., C.K., A.V., S.S., B.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.vW., M.S., D.S., G.C., P.Z., D.D., K.Z., M.M., M.T., D.T., A.K., P.S., T.J., M.B.-K, R.P., M.Sz., 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. 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.

                Article
                NIHMS1510061
                10.1038/s41588-018-0281-y
                6668343
                30578417
                07ef6c4b-cba7-4346-a534-c939a79bdbb9

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