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

Abstract

The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, in-creased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberra-tions 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 knock-out models. Here, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal uro-rectal 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.

Keywords: Array; Bladder; Cloacal; Epispadias; Exome; Exstrophy; Pathway.

Fig. (1)

a, b) boy and girl with epispadias; c, d) boy and girl with classic exstrophy of the bladder; e) boy with exstrophy of the cloaca(Ebert et al. 2009).