22q11.2 duplications in a UK cohort with bladder exstrophy-epispadias complex

The bladder exstrophy-epispadias complex (BEEC) comprises of a spectrum of anterior midline defects, all affecting the lower urinary tract, the external genitalia and the bony pelvis. In extreme cases, the gastrointestinal tract is also affected. The pathogenesis of BEEC is unclear but chromosomal aberrations have been reported. In particular, duplications of 22q11.2 have been identified in eight unrelated individuals with BEEC. The current study aimed to identify chromosomal copy number variants in BEEC. Analyses was performed using the Affymetrix Genome-wide SNP6.0 assay in 92 unrelated patients cared for by two UK pediatric urology centres. Three individuals had a 22q11.2 duplication, a significantly higher number than that found in a control group of 12,500 individuals with developmental delay who had undergone microarray testing (p<0.0001). Sequencing of CRKL, implicated in renal tract malformations in DiGeorge syndome critical region at 22q11, in 89 individuals with BEEC lacking 22q11 duplications revealed no pathogenic variants. To date, 22q11.2 duplication is the genetic variant most commonly associated with BEEC. This is consistent with the hypothesis that altered expression of a single, yet to be defined, gene therein is critical to the pathogenesis of this potentially devastating congenital disorder.