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

2012; Elsevier BV; Volume: 91; Issue: 6 Linguagem: Inglês

10.1016/j.ajhg.2012.10.007

1537-6605

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 Izzi, Beatrice Bianco, Marcin Zaniew, Hana Flögelová, Patricia L. Weng, Nilgun Kacak, Stefania Giberti, Maddalena Gigante, Adela Arapović, Kristina Drnašin, 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 W. State, Lorraine N. Clark, Marijan Saraga, Sandosh Padmanabhan, Anna F. Dominiczak, Tatiana Foroud, Loreto Gesualdo, Zoran Gucev, Landino Allegri, Anna Latos‐Bieleńska, Daniele Cusi, Francesco Scolari, Velibor Tasić, Hákon Hákonarson, Gian Marco Ghiggeri, Ali G. Gharavi,

Prenatal Screening and Diagnostics

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.