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-Cherchi^1, 2, Krzysztof Kiryluk¹, Katelyn E. Burgess¹, Monica Bodria³, Matthew G. Sampson⁵, Dexter Hadley⁴, Shannon N. Nees¹, Miguel Verbitsky¹, Brittany J. Perry¹, Roel Sterken¹, Vladimir J. Lozanovski⁶, Anna Materna-Kiryluk⁷, Cristina Barlassina^8, 9, Akshata Kini⁴, Valentina Corbani¹⁰, Alba Carrea³, Danio Somenzi¹¹, Corrado Murtas³, Nadica Ristoska-Bojkovska⁶, Claudia Izzi¹², Beatrice Bianco¹¹, Marcin Zaniew¹³, Hana Flogelova¹⁴, Patricia L. Weng¹, Nilgun Kacak¹, Stefania Giberti¹¹, Maddalena Gigante¹⁵, Adela Arapovic¹⁶, Kristina Drnasin¹⁷, Gianluca Caridi³, Simona Curioni⁸, Franca Allegri¹⁸, Anita Ammenti¹⁹, Stefania Ferretti²⁰, Vinicio Goj²¹, Luca Bernardo²¹, Vaidehi Jobanputra²², Wendy K. Chung²³, Richard P. Lifton²⁴, Stephan Sanders²⁴, Matthew State²⁴, Lorraine N. Clark²⁵, Marijan Saraga^16, 26, Sandosh Padmanabhan²⁷, Anna F. Dominiczak²⁷, Tatiana Foroud²⁸, Loreto Gesualdo¹⁵, Zoran Gucev⁶, Landino Allegri¹¹, Anna Latos-Bielenska⁷, Daniele Cusi⁸, Francesco Scolari¹², Velibor Tasic⁶, Hakon Hakonarson^4, 5, Gian Marco Ghiggeri³ and Ali G. Gharavi^1, ,  

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.