Birth defects research. Part A, Clinical and molecular teratology · 2014
Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Draaken Markus, Baudisch Friederike, Timmermann Bernd, Kuhl Heiner, Kerick Martin, Proske Judith, Wittler Lars, Pennimpede Tracie, Ebert Anne-Karoline, Rösch Wolfgang, Stein Raimund, Bartels Enrika, von Lowtzow Catharina, Boemers Thomas M, Herms Stefan, Gearhart John P, Lakshmanan Yegappan, Kockum Christina Clementsson, Holmdahl Gundela, Läckgren Göran, Nordenskjöld Agnetha, Boyadjiev Simeon A, Herrmann Bernhard G, Nöthen Markus M, Ludwig Michael, Reutter Heiko
Аннотация
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.
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.
Предметные рубрики MeSH
Adaptor Proteins, Signal TransducingAnimalsBladder ExstrophyCase-Control StudiesChromosomal Proteins, Non-HistoneChromosome DuplicationChromosomes, Human, Pair 22Embryo, MammalianEpispadiasFemaleHumansIn Situ HybridizationMaleMiceNuclear ProteinsOdds RatioOligonucleotide Array Sequence AnalysisSequence Analysis, DNATranscription FactorsUrethraUrinary Bladder