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

PubMed ID

30578417

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