The copy number variation landscape of congenital anomalies of the kidney and urinary tract

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 (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.

Comparative Study Between Functional MR Urography and Renal Scintigraphy to Evaluate Drainage Curves and Split Renal Function in Children With Congenital Anomalies of Kidney and Urinary Tract (CAKUT)

“…However, the advantage of MR in reducing exposure to ionizing radiation and in depicting fine anatomical details, which is extremely useful for surgical approach, makes this technique strongly recommended in CAKUT. Complex CAKUT cases should be addressed to a second or third level center for a three-dimensional diagnostic assessment and for the new precision medicine programs that will be offered in the next future simultaneously with knowledge from new generation data (40).…”

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

“…Two other genes residing at 16p11.2, TBX6 and MAZ, were associated previously with congenital defects of kidney and urinary tract [73,74], while GWAS have suggested TBX6 [23], MAPK3 [21] and INO80E [22] as potential candidates for AaM. Furthermore, the 14-gene cluster (distal to proximal: SPN, QPRT, ZG16, KIF22, PRRT2, MAZ, MVP, SEZ6L2, ASPHD1, KCTD13, TMEM219, TAOK2, INO80E, DOC2A) was shown to be under coordinated estrogen-mediated regulation [75].…”

Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review

“…It is possible these patients without reported eye manifestations did not have abnormal eye or ocular adnexa features, although we suspect the omission of reported eye features was more frequently related to the particular concentration of topics within each individual report. For example, an article titled " e copy number variation landscape of congenital anomalies of the kidney and urinary tract" by Miguel Verbitsky et al describes extrarenal malformations in a variety of patients with copy number variants (CNV), including 9 patients with confirmed 16p11.2 microdeletions; ophthalmic manifestations were not featured [26].…”