Isolated bladder exstrophy associated with a de novo 0.9 Mb microduplication on chromosome 19p13.12.
BACKGROUND
The exstrophy-epispadias complex (BEEC) is a urogenital birth defect of varying severity. The causes of the BEEC are likely to be heterogeneous, with individual environmental or genetic risk factors still being largely unknown. In this study, we aimed to identify de novo causative copy number variations (CNVs) that contribute to the BEEC.


METHODS
Array-based molecular karyotyping was performed to screen 110 individuals with BEEC. Promising CNVs were tested for de novo occurrence by investigating parental DNAs. Genes located in regions of rearrangements were prioritized through expression analysis in mice to be sequenced in the complete cohort, to identify high-penetrance mutations involving small sequence changes.


RESULTS
A de novo 0.9 Mb microduplication involving chromosomal region 19p13.12 was identified in a single patient. This region harbors 20 validated RefSeq genes, and in situ hybridization data showed specific expression of the Wiz gene in regions surrounding the cloaca and the rectum between GD 9.5 and 13.5. Sanger sequencing of the complete cohort did not reveal any pathogenic alterations affecting the coding region of WIZ.


CONCLUSIONS
The present study suggests chromosomal region 19p13.12 as possibly involved in the development of CBE, but further studies are needed to prove a causal relation. The spatiotemporal expression patterns determined for the genes encompassed suggest a role for Wiz in the development of the phenotype. Our mutation screening, however, could not confirm that WIZ mutations are a frequent cause of CBE, although rare mutations might be detectable in larger patient samples. 19p13.12, microduplication, bladder exstrophy-epispadias complex, array-based molecular karyotyping, in situ hybridization analysis, copy number variations, WIZ gene.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Markus
M
Draaken
Sadaf S
SS
Mughal
Tracie
T
Pennimpede
Stefanie
S
Wolter
Lars
L
Wittler
Anne-Karoline
AK
Ebert
Wolfgang
W
Rösch
Raimund
R
Stein
Enrika
E
Bartels
Dominik
D
Schmidt
Thomas M
TM
Boemers
Eberhard
E
Schmiedeke
Per
P
Hoffmann
Susanne
S
Moebus
Bernhard G
BG
Herrmann
Markus M
MM
Nöthen
Heiko
H
Reutter
Michael
M
Ludwig
D000818:Animals; D001483:Base Sequence; D001746:Bladder Exstrophy / Q000235:genetics*; D058674:Chromosome Duplication; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D059785:Karyotype; D051379:Mice; D017422:Sequence Analysis, DNA; D001743:Urinary Bladder / Q000002:abnormalities