Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy

Bladder exstrophy is a rare congenital malformation leaving the urinary bladder open in the midline of the abdomen at birth. There is a clear genetic background with chromosome aberrations, but so far, no consistent findings apart from 22q11-duplications detected in about 2%-3% of all patients. Some genes are implicated like the LZTR1, ISL1, CELSR3, and the WNT3 genes, but most are not explained molecularly. We have performed chromosomal microarray analysis on a cohort of 140 persons born with bladder exstrophy to look for submicroscopic chromosomal deletions and duplications. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and further 9 with unknown significance. Two findings were in regions linked to known syndromes, two findings involved the same gene (MCC), and all other findings were unique. A closer analysis suggests a few gene networks that are involved in the pathogenesis of bladder exstrophy; the WNT-signaling pathway, the chromosome 22q11 region, the RIT2 and POU families, and involvement of the Golgi apparatus. Bladder exstrophy is a rare malformation and is reported to be associated with several chromosome aberrations. Our data suggest involvement of some specific molecular pathways.

Automated summary

Bladder exstrophy is a rare congenital malformation with a clear genetic background. Chromosome aberrations, particularly 22q11-duplications, are commonly found in patients. Several genes, including LZTR1, ISL1, CELSR3, and WNT3, have been implicated in the disease, but many remain unexplained molecularly. Using chromosomal microarray analysis, we identified pathogenic or possibly pathogenic chromosomal deletions or duplications in a cohort of 140 bladder exstrophy patients, suggesting the involvement of specific molecular pathways such as the WNT-signaling pathway and the chromosome 22q11 region.