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.

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.

IntroductionDiagnosis of contrast induced-nephropathy (CIN) by a classic renal biomarker such as creatinine concentration can be delayed because of various factors that can influence this marker. Changes in new biomarkers such as neutrophil-gelatinase associated lipocalin (NGAL) and cystatin C are postulated to be more sensitive for recognizing patients prone to CIN-acute kidney injury (AKI).AimTo investigate the role of NGAL and cystatin C as early biomarkers in the diagnosis of kidney injury after cardiac catheterisation.Material and methodsThe study group consisted of 50 patients with congenital heart malformation admitted for scheduled cardiac catheterisation. The biomarkers serum creatinine, serum NGAL and serum cystatin C were tested at 5 time-points sequentially from start to 48 h after the procedure.ResultsSignificant changes were noted during the research in the serum creatinine concentration (p < 0.001) and serum NGAL concentration (p < 0.001). CIN-AKI, diagnosed by the modified Schwartz formula, occurred in 16 (32%) patients after 24 h and in 8 (16%) after 48 h. Subsequent analysis showed that serum creatinine significantly rose in the first 2 h of the study with simultaneous reduction in the eGFR. Maximum growth in serum NGAL occurred at 6 h after contrast administration and then returned to the baseline values at 24 h. Serum cystatin C level did not significantly change during the study.ConclusionsWe observed a transient decrease in eGFR and a rise of serum NGAL after 2 h but NGAL was most pronounced at 6 h after the procedure. The potential role of cystatin C as a biomarker of CIN-AKI was not proved.

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). "

No abstract