The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Miguel Verbitsky, Rik Westland, Alejandra Perez, Krzysztof Kiryluk, Qingxue Liu, Priya Krithivasan, Adele Mitrotti, David A Fasel, Ekaterina Batourina, Matthew G Sampson, Monica Bodria, Max Werth, Charlly Kao, Jeremiah Martino, Valentina P Capone, Asaf Vivante, Shirlee Shril, Byum Hee Kil, Maddalena Marasà, Jun Y ZhangYoung-Ji Na, Tze Y Lim, Dina Ahram, Patricia L Weng, Erin L Heinzen, Alba Carrea, Giorgio Piaggio, Loreto Gesualdo, Valeria Manca, Giuseppe Masnata, Maddalena Gigante, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E van Wijk, Marijan Saraga, Domenico Santoro, Giovanni Conti, Pasquale Zamboli, Hope White, Dorota Drozdz, Katarzyna Zachwieja, Monika Miklaszewska, Marcin Tkaczyk, Daria Tomczyk, Anna Krakowska, Przemyslaw Sikora, Tomasz Jarmoliński, Maria K Borszewska-Kornacka, Robert Pawluch, Maria Szczepanska, Piotr Adamczyk, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, Mark G Dobson, John M Darlow, Prem Puri, David E Barton, Susan L Furth, Bradley A Warady, Zoran Gucev, Vladimir J Lozanovski, Velibor Tasic, Isabella Pisani, Landino Allegri, Lida M Rodas, Josep M Campistol, Cécile Jeanpierre, Shumyle Alam, Pasquale Casale, Craig S Wong, Fangming Lin, Débora M Miranda, Eduardo A Oliveira, Ana Cristina Simões-E-Silva, Jonathan M Barasch, Brynn Levy, Nan Wu, Friedhelm Hildebrandt, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna-Kiryluk, Feng Zhang, Hakon Hakonarson, Virginia E Papaioannou, Cathy L Mendelsohn, Ali G Gharavi, Simone Sanna-Cherchi

Research output: Contribution to journalArticle

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Original languageEnglish
Pages (from-to)117-127
Number of pages11
JournalNature Genetics
Volume51
Issue number1
DOIs
Publication statusPublished - Jan 2019

Keywords

  • Chromosome Deletion
  • DNA Copy Number Variations/genetics
  • Female
  • Genetic Predisposition to Disease/genetics
  • Genome-Wide Association Study/methods
  • Humans
  • Kidney/abnormalities
  • Male
  • Urinary Tract/abnormalities
  • Urogenital Abnormalities/genetics
  • Vesico-Ureteral Reflux/genetics

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  • Cite this

    Verbitsky, M., Westland, R., Perez, A., Kiryluk, K., Liu, Q., Krithivasan, P., Mitrotti, A., Fasel, D. A., Batourina, E., Sampson, M. G., Bodria, M., Werth, M., Kao, C., Martino, J., Capone, V. P., Vivante, A., Shril, S., Kil, B. H., Marasà, M., ... Sanna-Cherchi, S. (2019). The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nature Genetics, 51(1), 117-127. https://doi.org/10.1038/s41588-018-0281-y