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 (i.e. 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; 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.

Bladder cancer is the sixth most common cancer in humans. This heterogeneous set of lesions including urothelial carcinoma (Uca) and squamous cell carcinoma (SCC) arise from the urothelium, a stratified epithelium composed of K5-expressing basal cells, intermediate cells and umbrella cells. Superficial Uca lesions are morphologically distinct and exhibit different clinical behaviours: carcinoma in situ (CIS) is a flat aggressive lesion, whereas papillary carcinomas are generally low-grade and non-invasive. Whether these distinct characteristics reflect different cell types of origin is unknown. Here we show using lineage tracing in a murine model of carcinogenesis that intermediate cells give rise primarily to papillary lesions, whereas K5-basal cells are likely progenitors of CIS, muscle-invasive lesions and SCC depending on the genetic background. Our results provide a cellular and genetic basis for the diversity in bladder cancer lesions and provide a possible explanation for their clinical and morphological differences.

SUMMARYUrinary tract development depends on a complex series of events in which the ureter moves from its initial branch point on the nephric duct (ND) to its final insertion site in the cloaca (the primitive bladder and urethra). Defects in this maturation process can result in malpositioned ureters and hydronephrosis, a common cause of renal disease in children. Here, we report that insertion of the ND into the cloaca is an unrecognized but crucial step that is required for proper positioning of the ureter and that depends on Ret signaling. Analysis of Ret mutant mice at birth reveals hydronephrosis and defective ureter maturation, abnormalities that our results suggest are caused, at least in part, by delayed insertion of the ND. We find a similar set of malformations in mutants lacking either Gata3 or Raldh2. We show that these factors act in parallel to regulate ND insertion via Ret. Morphological analysis of ND extension in wild-type embryos reveals elaborate cellular protrusions at ND tips that are not detected in Ret, Gata3 or Raldh2 mutant embryos, suggesting that these protrusions may normally be important for fusion with the cloaca. Together, our studies reveal a novel Ret-dependent event, ND insertion, that, when abnormal, can cause obstruction and hydronephrosis at birth; whether ND defects underlie similar types of urinary tract abnormalities in humans is an interesting possibility.

BackgroundVesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.MethodsA diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry.ResultsAltogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10−8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41–6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10–9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.ConclusionsThese data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

In the version of Fig. 4b initially published, there was a calculation error in the estimates of shared environmental variance (c 2 ) for MaTCH functional domains. For all MaTCH functional domains except the 'all traits' functional domain, the estimate of c 2 was calculated with monozygotic twin correlation (r MZ ) and dizygotic twin correlation (r DZ ) for each functional domain provided by the MaTCH website (http://match.ctglab.nl/). The c 2 value should have been estimated as c 2 = 2r DZ -r MZ but, owing to a coding error, was erroneously estimated as c 2 = 2r DZ -r DZ . The c 2 estimate for the 'all traits' functional domain was correct in the version of the article initially published, and therefore no conclusions are affected; however, the contribution of c 2 among MaTCH functional domains is decreased. The authors thank G. Gibson and M. Nordborg for pointing out the error.To correct this error, Fig. 4 has been revised to include corrected c 2 estimates in the data in panel b as well as to include the numbers of phenotypes in both the CaTCH and MaTCH functional domains in the y axes of panels a and b. The number of phenotypes for each MaTCH functional domain in Fig. 4 is based on the number of phenotypes for which h 2 and c 2 were estimated with twin correlation (r MZ and r DZ ) taken from the MaTCH website. The total numbers of phenotypes within each MaTCH functional domain where h 2 /c 2 were estimated with either twin correlation or variance component models (ACE) and can be found in Supplementary Table 1. The legend of Fig. 4 has been revised to include descriptions of the red and blue values and a description of the numbers of phenotypes in the y axes in panels a and b. In the Results section, the description of Fig. 4b reading "For c 2 , the 95% CI from CaTCH estimates overlapped with the 95% CI from the MaTCH estimates for only the infection domain (Fig. 4b)" has been changed to "For c 2 , the 95% CI from CaTCH estimates overlapped with the 95% CI from the MaTCH estimates for 11 out of 21 functional domains, namely cardiovascular, dermatological, endocrine, gastrointestinal, hematological, immunological, infection, metabolic, psychiatric, reproduction, and skeletal functional domains (Fig. 4b). "