Copy-number disorders are a common cause of congenital kidney malformations

Simone Sanna-Cherchi, Krzysztof Kiryluk, Katelyn E. Burgess, Monica Bodria, Matthew G. Sampson, Dexter Hadley, Shannon N. Nees, Miguel Verbitsky, Brittany J. Perry, Roel Sterken, Vladimir J. Lozanovski, Anna Materna-Kiryluk, Cristina Barlassina, Akshata Kini, Valentina Corbani, Alba Carrea, Danio Somenzi, Corrado Murtas, Nadica Ristoska-Bojkovska, Claudia IzziBeatrice Bianco, Marcin Zaniew, Hana Flogelova, Patricia L. Weng, Nilgun Kacak, Stefania Giberti, Maddalena Gigante, Adela Arapovic, Kristina Drnasin, Gianluca Caridi, Simona Curioni, Franca Allegri, Anita Ammenti, Stefania Ferretti, Vinicio Goj, Luca Bernardo, Vaidehi Jobanputra, Wendy K. Chung, Richard P. Lifton, Stephan Sanders, Matthew State, Lorraine N. Clark, Marijan Saraga, Sandosh Padmanabhan, Anna F. Dominiczak, Tatiana Foroud, Loreto Gesualdo, Zoran Gucev, Landino Allegri, Anna Latos-Bielenska, Daniele Cusi, Francesco Scolari, Velibor Tasic, Hakon Hakonarson, Gian Marco Ghiggeri, Ali G. Gharavi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)987-997
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Dec 7 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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