lunes, 26 de noviembre de 2012

AJHG - Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations

AJHG - Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations

Copyright © 2012 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, 15 November 2012
doi:10.1016/j.ajhg.2012.10.007
Article

Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations

Simone Sanna-Cherchi12Krzysztof Kiryluk1Katelyn E. Burgess1Monica Bodria3Matthew G. Sampson5Dexter Hadley4Shannon N. Nees1Miguel Verbitsky1Brittany J. Perry1Roel Sterken1Vladimir J. Lozanovski6Anna Materna-Kiryluk7Cristina Barlassina89Akshata Kini4Valentina Corbani10Alba Carrea3Danio Somenzi11Corrado Murtas3Nadica Ristoska-Bojkovska6Claudia Izzi12Beatrice Bianco11Marcin Zaniew13Hana Flogelova14Patricia L. Weng1Nilgun Kacak1Stefania Giberti11Maddalena Gigante15Adela Arapovic16Kristina Drnasin17Gianluca Caridi3Simona Curioni8Franca Allegri18Anita Ammenti19Stefania Ferretti20Vinicio Goj21Luca Bernardo21Vaidehi Jobanputra22Wendy K. Chung23Richard P. Lifton24Stephan Sanders24Matthew State24Lorraine N. Clark25Marijan Saraga1626Sandosh Padmanabhan27Anna F. Dominiczak27Tatiana Foroud28Loreto Gesualdo15Zoran Gucev6Landino Allegri11Anna Latos-Bielenska7Daniele Cusi8Francesco Scolari12Velibor Tasic6Hakon Hakonarson45Gian Marco Ghiggeri3 and Ali G. Gharavi1Go To Corresponding Author 
1 Division of Nephrology, Columbia University, New York, NY 10023, USA
2 Department of Internal Medicine, St. Luke’s-Roosevelt Hospital Center, New York, NY 10019, USA
3 Division of Nephrology, Dialysis, and Transplantation, G. Gaslini Institute, Genoa 16147, Italy
4 Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA
5 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA
6 Division of Pediatric Nephrology, University Children’s Hospital, Skopje 1000, Macedonia
7 Polish Registry of Congenital Malformations, Poznan 60352, Poland
8 Division of Nephrology, San Paolo Hospital, Milan 20142, Italy
9 Department of Medicine, Surgery, and Dentistry, University of Milan, Milan 20142, Italy
10 SC of Nephrology and Dialysis, Sant’Andrea Hospital, La Spezia 19100, Italy
11 Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Parma 43100, Italy
12 Chair of Nephrology, University of Brescia and Division of Nephrology, Montichiari Hospital, Montichiari 25018, Italy
13 Department of Pediatrics, Nephrology and Toxicology, District Children Hospital, Szczecin 70111, Poland
14 Faculty of Medicine, Palacky University, Olomouc 77200, Czech Republic
15 Department of Biomedical Sciences, University of Foggia, Foggia 71100, Italy
16 Department of Pediatrics, University Hospital of Split, Split 21000, Croatia
17 Pediatric Outpatient Clinic, Solin 21210, Croatia
18 Department of Clinical Sciences, University of Parma, Parma 43100, Italy
19 Department of Pediatrics, University of Parma, Parma 43100, Italy
20 Division of Urology, Parma University Hospital, Parma 43100, Italy
21 SC of Pediatrics, Fatebenefratelli Hospital, Milan 21121, Italy
22 Department of Pathology, Columbia University, New York, NY 10032, USA
23 Department of Pediatrics, Division of Clinical Genetics, Columbia University, New York, NY 10032, USA
24 Department of Genetics, Yale University, New Haven, CT 06520, USA
25 Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY 10032, USA
26 University of Split, School of Medicine, Split 21000, Croatia
27 Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G128QQ, UK
28 Indiana University School of Medicine, Indianapolis, IN 46202, USA
Corresponding author

Abstract

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10−11). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10−58). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

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