Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.
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.
Division of Nephrology, Columbia University, New York, New York, USA.|Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Rik
R
Westland
Division of Nephrology, Columbia University, New York, New York, USA.
Miguel
M
Verbitsky
Division of Nephrology, Columbia University, New York, New York, USA.|Department of Anatomy, Histology, and Embryology, School of Medicine, University of Split, Split, Croatia.
Katarina
K
Vukojevic
Division of Nephrology, Columbia University, New York, New York, USA.
Brittany J
BJ
Perry
Division of Nephrology, Columbia University, New York, New York, USA.
David A
DA
Fasel
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Petra J G
PJ
Zwijnenburg
Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Arend
A
Bökenkamp
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Johan J P
JJ
Gille
Department of Anatomy, Histology, and Embryology, School of Medicine, University of Split, Split, Croatia.
Mirna
M
Saraga-Babic
Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy.
Gian Marco
GM
Ghiggeri
Department of Pathology, Columbia University, New York, New York, USA.
Vivette D
VD
D'Agati
Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
Michiel F
MF
Schreuder
Division of Nephrology, Columbia University, New York, New York, USA.
Ali G
AG
Gharavi
Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Joanna A E
JA
van Wijk
Division of Nephrology, Columbia University, New York, New York, USA.
Simone
S
Sanna-Cherchi