Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.
The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5–15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.
Nayia
N
Nicolaou
Sara L
SL
Pulit
Isaac J
IJ
Nijman
Glen R
GR
Monroe
Wout F J
WF
Feitz
Michiel F
MF
Schreuder
Albertien M
AM
van Eerde
Tom P V M
TP
de Jong
Jacques C
JC
Giltay
Bert
B
van der Zwaag
Marlies R
MR
Havenith
Susan
S
Zwakenberg
Loes F M
LF
van der Zanden
Geert
G
Poelmans
Elisabeth A M
EA
Cornelissen
Marc R
MR
Lilien
Barbara
B
Franke
Nel
N
Roeleveld
Iris A L M
IA
van Rooij
Edwin
E
Cuppen
Ernie M H F
EM
Bongers
Rachel H
RH
Giles
Nine V A M
NV
Knoers
Kirsten Y
KY
Renkema
D005091:Exons; D017353:Gene Deletion; D006801:Humans; D017422:Sequence Analysis, DNA; D014564:Urogenital Abnormalities / Q000235:genetics*