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

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.Birth Defects Research (Part A) 100:512-517, 2014.V C 2014 Wiley Periodicals, Inc.

Chromosomal microarray analysis in fetuses with congenital anomalies of the kidney and urinary tract: A prospective cohort study and meta‐analysis

“…CAKUT, although rare, has been reported in several cases with 22q11.2 duplication . The association between bladder exstrophy and 22q11.2 duplication had been demonstrated, and the genes CRKL (OMIM 602007), THAP7 (OMIM 609518), and LZTR1 (OMIM 600574) in a 414‐kb critical region have been reported to be candidate genes . Of note, the gene CRKL was thought to be a candidate gene for CAKUT for both 22q11.2 deletion and 22q11.2 duplication.…”

“…(OMIM 609518), and LZTR1 (OMIM 600574) in a 414-kb critical region have been reported to be candidate genes. 36 VOUS has always been a concern in the CMA analysis, especially in the prenatal cases. The detection of VOUS could lead to challenges in counseling and parental anxiety.…”

Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development

“…Anomalies and Is Expressed During GU Development. By retrospectively analyzing 22q11.2 patients from the DECIPHER database, previously published literature (18), and patient data acquired from aCGH previously performed by our laboratory (14), we compiled an overlap map of patients with 22q11.2 dosage variation who also exhibit GU phenotypes (Fig. 1).…”

Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene

“…Most chromosomal regions, genes and pathways have been identified in isolated cases or by association studies. The only recurrent and most frequently detected genetic aberration found in BEEC cases is the recurrent 3 Mb large tandem 22q11.2 microduplication (Draaken et al, ,; Lundin et al, ; Pierquin & Uwineza, ). We previously screened 36 patients born with bladder exstrophy for copy number variants and reported two unrelated cases carrying the 22q11.2 microduplication (one de novo and one inherited) (Lundin et al, ).…”