1. Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations
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Lorraine N. Clark, Krzysztof Kiryluk, Francesco Scolari, Gian Marco Ghiggeri, Marcin Zaniew, Anna Materna-Kiryluk, Valentina Corbani, Anita Ammenti, Stephen Sanders, Stefania Giberti, Hana Flögelová, Daniele Cusi, Ali G. Gharavi, Maddalena Gigante, Simona Curioni, Kristina Drnasin, Hakon Hakonarson, Akshata Kini, Landino Allegri, Simone Sanna-Cherchi, Roel Sterken, Luca Bernardo, Claudia Izzi, Nadica Ristoska-Bojkovska, Adela Arapović, Loreto Gesualdo, Brittany J. Perry, Sandosh Padmanabhan, Matthew W. State, Vladimir J Lozanovski, Alba Carrea, Cristina Barlassina, Dexter Hadley, Matthew G. Sampson, Richard P. Lifton, Tatiana Foroud, Wendy K. Chung, Gianluca Caridi, Miguel Verbitsky, Shannon N. Nees, Zoran Gucev, Nilgun Kacak, Marijan Saraga, Vinicio Goj, Katelyn Elizabeth Burgess, Velibor Tasic, Monica Bodria, Patricia L. Weng, Stefania Ferretti, Beatrice Bianco, Danio Somenzi, Corrado Murtas, Anna Latos-Bielenska, Vaidehi Jobanputra, Franca Allegri, and Anna F. Dominiczak
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Kidney Disease ,Genotype ,DNA Copy Number Variations ,Population ,030232 urology & nephrology ,Renal and urogenital ,Locus (genetics) ,Biology ,Medical and Health Sciences ,Article ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Genetics(clinical) ,MULTIPLE MALFORMATIONS ,Aetiology ,education ,Genetics (clinical) ,Genetic Association Studies ,030304 developmental biology ,Chromosome Aberrations ,Genetics & Heredity ,0303 health sciences ,education.field_of_study ,Prevention ,Human Genome ,Case-control study ,Molecular Sequence Annotation ,copy -number disorders ,congenital kidney malformations ,Biological Sciences ,HNF1B ,3. Good health ,Brain Disorders ,Case-Control Studies ,Cohort ,Kidney Diseases ,Kidney malformations - 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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