TY - JOUR
T1 - Classic bladder exstrophy
T2 - Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region
AU - Draaken, Markus
AU - Baudisch, Friederike
AU - Timmermann, Bernd
AU - Kuhl, Heiner
AU - Kerick, Martin
AU - Proske, Judith
AU - Wittler, Lars
AU - Pennimpede, Tracie
AU - Ebert, Anne Karoline
AU - Rösch, Wolfgang
AU - Stein, Raimund
AU - Bartels, Enrika
AU - von Lowtzow, Catharina
AU - Boemers, Thomas M.
AU - Herms, Stefan
AU - Gearhart, John P.
AU - Lakshmanan, Yegappan
AU - Kockum, Christina Clementsson
AU - Holmdahl, Gundela
AU - Läckgren, Göran
AU - Nordenskjöld, Agnetha
AU - Boyadjiev, Simeon A.
AU - Herrmann, Bernhard G.
AU - Nöthen, Markus M.
AU - Ludwig, Michael
AU - Reutter, Heiko
PY - 2014/6
Y1 - 2014/6
N2 - Background: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. Methods: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. Results: New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes. Conclusion: Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation.
AB - Background: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. Methods: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. Results: New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes. Conclusion: Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation.
KW - Bladder exstrophy and epispadias complex (BEEC)
KW - Chromosome 22q11.2
KW - Classic bladder exstrophy (CBE)
KW - Copy number variation
KW - Duplication
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U2 - 10.1002/bdra.23249
DO - 10.1002/bdra.23249
M3 - Article
C2 - 24764164
AN - SCOPUS:84903126733
SN - 1542-0752
VL - 100
SP - 512
EP - 517
JO - Birth Defects Research Part A - Clinical and Molecular Teratology
JF - Birth Defects Research Part A - Clinical and Molecular Teratology
IS - 6
ER -