Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5–10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population.

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.

The congenital malformation bladder exstrophy and epispadias complex involves multiple organs and includes 3 subtypes: epispadias, classic bladder exstrophy, and cloacal exstrophy. The risk of urinary bladder cancer is known to be higher in individuals with classic bladder exstrophy and appears at a younger age compared with the general population. Purpose: The purpose of this study was to evaluate urinary bladder cancer in individuals with bladder exstrophy and epispadias complex. Materials and Methods: We performed 2 studies, a Swedish register-based case series reporting 12 novel cases and a systematic review summarizing published cases thus far. MEDLINE, EMBASE, Web of Science, and Google Scholar were searched in January 2022 following the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Publications reporting at least 1 case of bladder exstrophy and epispadias complex with urinary bladder cancer were eligible. Ninety-seven publications were included, reporting 165 cases. Results: The main result from the register study was the tumors being predominantly urothelial. Conversely, earlier published cases from the literature had a nonurothelial tumor type in 95%, whereof the majority were adenocarcinomas. Both substudies consistently indicate a young age at cancer diagnosis, with the majority being younger than 65 years. Conclusions: Urinary bladder cancer affects individuals with bladder exstrophy and epispadias complex at a young age. The most common tumor type in the register study is urothelial. The divergence between the 2 substudies in tumor types could reflect a slightly older age in our case series, likewise a possible publication bias.

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.