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.

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

No abstract

No abstract