Creator(s)

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. Zhang
Young-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, Children's Mercy HospitalFollow
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

Document Type

Article

Publication Date

1-1-2019

Identifier

PMCID: PMC6668343 DOI: 10.1038/s41588-018-0281-y

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.

Journal Title

Nature genetics

Volume

51

Issue

1

First Page

117

Last Page

127

MeSH Keywords

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

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