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Classic Bladder Exstrophy: Frequent 22q11.21 Duplications and Definition of a 414 kb Phenocritical Region

Draaken, Markus; Baudisch, Friederike; Timmermann, Bernd; Kuhl, Heiner; Kerick, Martin; Proske, Judith; Wittler, Lars; Pennimpede, Tracie; Ebert, Anne-Karoline and Roesch, Wolfgang, et al. (2014) In Birth Defects Research. Clinical and Molecular Teratology 100(6). p.512-517
Abstract
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... (More)
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. (C) 2014 Wiley Periodicals, Inc. (Less)
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chromosome 22q11.2, duplication, bladder exstrophy and epispadias, complex (BEEC), classic bladder exstrophy (CBE), copy number variation
in
Birth Defects Research. Clinical and Molecular Teratology
volume
100
issue
6
pages
512 - 517
publisher
John Wiley & Sons
external identifiers
  • wos:000338036300008
  • scopus:84903126733
ISSN
1542-0760
DOI
10.1002/bdra.23249
language
English
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yes
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e51970ce-497a-4686-b532-1fd5f7a26d0c (old id 4609206)
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2014-09-01 07:40:54
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2017-05-28 03:15:31
@article{e51970ce-497a-4686-b532-1fd5f7a26d0c,
  abstract     = {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. (C) 2014 Wiley Periodicals, Inc.},
  author       = {Draaken, Markus and Baudisch, Friederike and Timmermann, Bernd and Kuhl, Heiner and Kerick, Martin and Proske, Judith and Wittler, Lars and Pennimpede, Tracie and Ebert, Anne-Karoline and Roesch, Wolfgang and Stein, Raimund and Bartels, Enrika and von Lowtzow, Catharina and Boemers, Thomas M. and Herms, Stefan and Gearhart, John P. and Lakshmanan, Yegappan and Clementson Kockum, Christina and Holmdahl, Gundela and Lackgren, Goran and Nordenskjold, Agnetha and Boyadjiev, Simeon A. and Herrmann, Bernhard G. and Noethen, Markus M. and Ludwig, Michael and Reutter, Heiko},
  issn         = {1542-0760},
  keyword      = {chromosome 22q11.2,duplication,bladder exstrophy and epispadias,complex (BEEC),classic bladder exstrophy (CBE),copy number variation},
  language     = {eng},
  number       = {6},
  pages        = {512--517},
  publisher    = {John Wiley & Sons},
  series       = {Birth Defects Research. Clinical and Molecular Teratology},
  title        = {Classic Bladder Exstrophy: Frequent 22q11.21 Duplications and Definition of a 414 kb Phenocritical Region},
  url          = {http://dx.doi.org/10.1002/bdra.23249},
  volume       = {100},
  year         = {2014},
}