Dataset Information

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 (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.

SUBMITTER: Verbitsky M

PROVIDER: S-EPMC6668343 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Verbitsky Miguel M Westland Rik R Perez Alejandra A Kiryluk Krzysztof K Liu Qingxue Q Krithivasan Priya P Mitrotti Adele A Fasel David A DA Batourina Ekaterina E Sampson Matthew G MG Bodria Monica M Werth Max M Kao Charlly C Martino Jeremiah J Capone Valentina P VP Vivante Asaf A Shril Shirlee S Kil Byum Hee BH Marasà Maddalena M Zhang Jun Y JY Na Young-Ji YJ Lim Tze Y TY Ahram Dina D Weng Patricia L PL Heinzen Erin L EL Carrea Alba A Piaggio Giorgio G Gesualdo Loreto L Manca Valeria V Masnata Giuseppe G Gigante Maddalena M Cusi Daniele D Izzi Claudia C Scolari Francesco F van Wijk Joanna A E JAE Saraga Marijan M Santoro Domenico D Conti Giovanni G Zamboli Pasquale P White Hope H Drozdz Dorota D Zachwieja Katarzyna K Miklaszewska Monika M Tkaczyk Marcin M Tomczyk Daria D Krakowska Anna A Sikora Przemyslaw P Jarmoliński Tomasz T Borszewska-Kornacka Maria K MK Pawluch Robert R Szczepanska Maria M Adamczyk Piotr P Mizerska-Wasiak Malgorzata M Krzemien Grazyna G Szmigielska Agnieszka A Zaniew Marcin M Dobson Mark G MG Darlow John M JM Puri Prem P Barton David E DE Furth Susan L SL Warady Bradley A BA Gucev Zoran Z Lozanovski Vladimir J VJ Tasic Velibor V Pisani Isabella I Allegri Landino L Rodas Lida M LM Campistol Josep M JM Jeanpierre Cécile C Alam Shumyle S Casale Pasquale P Casale Pasquale P Wong Craig S CS Lin Fangming F Miranda Débora M DM Oliveira Eduardo A EA Simões-E-Silva Ana Cristina AC Barasch Jonathan M JM Levy Brynn B Wu Nan N Hildebrandt Friedhelm F Ghiggeri Gian Marco GM Latos-Bielenska Anna A Materna-Kiryluk Anna A Zhang Feng F Hakonarson Hakon H Papaioannou Virginia E VE Mendelsohn Cathy L CL Gharavi Ali G AG Sanna-Cherchi Simone S

Nature genetics 20181221 1

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) h ...[more]

PMID: 30578417

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Project description:Most congenital anomalies of the kidney and urinary tract (CAKUT) are sporadic, but familial occurrence has been described, suggesting a genetic contribution. Copy‑number variations (CNVs) were detected in patients with CAKUT to identify possible novel genomic regions associated with CAKUT. CNVs were investigated in 7 children with CAKUT from three unrelated families using array comparative genomic hybridization: female monozygotic twins with bilateral duplex collecting system/vesicoureteral reflux (VUR)/unilateral renal hypodyspasia (URHD); two male siblings with VUR/URHD; 3 male second cousins, one with bilateral VUR/URHD, one with bilateral VUR and one with ureterovesical junction obstruction (UVJO). Five patients had a normal constitution of CNVs, one had a duplication of 0.2 Mb on the 5q‑arm (5q23.3), probably unrelated to CAKUT, and one with UVJO had a 1.4 Mb deletion on the 17q‑arm (17q12) which includes a known CAKUT gene, HNF1B. The phenotype of HNF1B deletion was extended including renal magnesium wasting. A higher coverage in transposable elements (TEs) was found in the deleted region compared with the expected density in any random genomic region. Notably, the 5' breakpoint was mapped within a solo long terminal repeat (LTR) sequence. Moreover, highly similar members of solo LTR and mammalian interspersed repetitive (MIR) elements, as well as nucleotide sequence microhomology were detected at the breakpoint regions. In conclusion, the deletion detected in one patient suggests this genomic imbalance as causative for UVJO. A not very well known phenotype of HNF1B deletion resulting in both low urinary tract malformations and renal wasting of magnesium was described. The high load in TEs of the deleted region, the presence of highly similar elements, and the microhomology found at breakpoint regions may have contributed to the generation of the deletion. CNV analysis could reveal novel causative genomic regions in patients with CAKUT, and further studies in larger cohorts are needed.

Dataset Information

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

Publications

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

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