Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region

Markus Draaken, Friederike Baudisch, Bernd Timmermann, Heiner Kuhl, Martin Kerick, Judith Proske, Lars Wittler, Tracie Pennimpede, Anne Karoline Ebert, Wolfgang Rösch, Raimund Stein, Enrika Bartels, Catharina von Lowtzow, Thomas M. Boemers, Stefan Herms, John P. Gearhart, Yegappan Lakshmanan, Christina Clementsson Kockum, Gundela Holmdahl, Göran LäckgrenAgnetha Nordenskjöld, Simeon Boyd, Bernhard G. Herrmann, Markus M. Nöthen, Michael Ludwig, Heiko Reutter

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)512-517
Number of pages6
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Issue number6
StatePublished - 2014


  • Bladder exstrophy and epispadias complex (BEEC)
  • Chromosome 22q11.2
  • Classic bladder exstrophy (CBE)
  • Copy number variation
  • Duplication

ASJC Scopus subject areas

  • Developmental Biology
  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Medicine(all)


Dive into the research topics of 'Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region'. Together they form a unique fingerprint.

Cite this