Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes

The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the urorectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, increased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberrations were suggestive of causative genetic factors, the recent identification of copy number variations (CNVs), susceptibility regions and genes through the systematic application of array based analysis, candidate gene and genome-wide association studies (GWAS) provide strong evidence. These findings in human BEEC cohorts are underscored by the recent description of BEEC(-like) murine knockout models. Here, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal urorectal development leading to the BEEC, demonstrating the importance of ISL1-pathway in human and mouse and propose SLC20A1 and CELSR3 as the first BEEC candidate genes, identified through systematic whole-exome sequencing (WES) in BEEC patients.