Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney

Rik Westland, Miguel Verbitsky, Katarina Vukojevic, Brittany J. Perry, David A. Fasel, Petra J G Zwijnenburg, Arend Bökenkamp, Johan J P Gille, Mirna Saraga-Babic, Gian Marco Ghiggeri, Vivette D. D'Agati, Michiel F. Schreuder, Ali G. Gharavi, Joanna A E Van Wijk, Simone Sanna-Cherchi

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

Original languageEnglish
Pages (from-to)1402-1410
Number of pages9
JournalKidney International
Volume88
Issue number6
DOIs
Publication statusPublished - Dec 1 2015

Fingerprint

Kidney
Genes
Urinary Tract
Phenotype
Haploinsufficiency
Population Control
Transcriptome
Computer Simulation
Cohort Studies
Cakut
Databases
Mutation

Keywords

  • Child
  • Congenital anomalies of the kidney and urinary tract
  • Copy number variation
  • Genetics
  • Renal hypodysplasia

ASJC Scopus subject areas

  • Nephrology

Cite this

Westland, R., Verbitsky, M., Vukojevic, K., Perry, B. J., Fasel, D. A., Zwijnenburg, P. J. G., ... Sanna-Cherchi, S. (2015). Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney International, 88(6), 1402-1410. https://doi.org/10.1038/ki.2015.239

Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. / Westland, Rik; Verbitsky, Miguel; Vukojevic, Katarina; Perry, Brittany J.; Fasel, David A.; Zwijnenburg, Petra J G; Bökenkamp, Arend; Gille, Johan J P; Saraga-Babic, Mirna; Ghiggeri, Gian Marco; D'Agati, Vivette D.; Schreuder, Michiel F.; Gharavi, Ali G.; Van Wijk, Joanna A E; Sanna-Cherchi, Simone.

In: Kidney International, Vol. 88, No. 6, 01.12.2015, p. 1402-1410.

Research output: Contribution to journalArticle

Westland, R, Verbitsky, M, Vukojevic, K, Perry, BJ, Fasel, DA, Zwijnenburg, PJG, Bökenkamp, A, Gille, JJP, Saraga-Babic, M, Ghiggeri, GM, D'Agati, VD, Schreuder, MF, Gharavi, AG, Van Wijk, JAE & Sanna-Cherchi, S 2015, 'Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney', Kidney International, vol. 88, no. 6, pp. 1402-1410. https://doi.org/10.1038/ki.2015.239
Westland, Rik ; Verbitsky, Miguel ; Vukojevic, Katarina ; Perry, Brittany J. ; Fasel, David A. ; Zwijnenburg, Petra J G ; Bökenkamp, Arend ; Gille, Johan J P ; Saraga-Babic, Mirna ; Ghiggeri, Gian Marco ; D'Agati, Vivette D. ; Schreuder, Michiel F. ; Gharavi, Ali G. ; Van Wijk, Joanna A E ; Sanna-Cherchi, Simone. / Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. In: Kidney International. 2015 ; Vol. 88, No. 6. pp. 1402-1410.
@article{4d0a9f75ef224174a1d11ec58b5c2f80,
title = "Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney",
abstract = "Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.",
keywords = "Child, Congenital anomalies of the kidney and urinary tract, Copy number variation, Genetics, Renal hypodysplasia",
author = "Rik Westland and Miguel Verbitsky and Katarina Vukojevic and Perry, {Brittany J.} and Fasel, {David A.} and Zwijnenburg, {Petra J G} and Arend B{\"o}kenkamp and Gille, {Johan J P} and Mirna Saraga-Babic and Ghiggeri, {Gian Marco} and D'Agati, {Vivette D.} and Schreuder, {Michiel F.} and Gharavi, {Ali G.} and {Van Wijk}, {Joanna A E} and Simone Sanna-Cherchi",
year = "2015",
month = "12",
day = "1",
doi = "10.1038/ki.2015.239",
language = "English",
volume = "88",
pages = "1402--1410",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney

AU - Westland, Rik

AU - Verbitsky, Miguel

AU - Vukojevic, Katarina

AU - Perry, Brittany J.

AU - Fasel, David A.

AU - Zwijnenburg, Petra J G

AU - Bökenkamp, Arend

AU - Gille, Johan J P

AU - Saraga-Babic, Mirna

AU - Ghiggeri, Gian Marco

AU - D'Agati, Vivette D.

AU - Schreuder, Michiel F.

AU - Gharavi, Ali G.

AU - Van Wijk, Joanna A E

AU - Sanna-Cherchi, Simone

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

AB - Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

KW - Child

KW - Congenital anomalies of the kidney and urinary tract

KW - Copy number variation

KW - Genetics

KW - Renal hypodysplasia

UR - http://www.scopus.com/inward/record.url?scp=84951567763&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951567763&partnerID=8YFLogxK

U2 - 10.1038/ki.2015.239

DO - 10.1038/ki.2015.239

M3 - Article

AN - SCOPUS:84951567763

VL - 88

SP - 1402

EP - 1410

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 6

ER -