Microduplications At 22q11.21 are Associated with Classic Bladder Exstrophy

Abstract

Purpose Classic exstrophy of the bladder (CBE) is part of the exstrophy-epispadias complex (EEC), a spectrum of urogenital anomalies in which part or all of the distal urinary tract fails to close. Familial occurrence has been observed, and previous studies have suggested an underlying multifactorial mode of inheritance. To date, no causative genetic or non-genetic factor has been unequivocally identified in humans. The present study aimed to identify microaberrations characterized by loss or gain of genomic material that contribute to the EEC at a genome-wide level. Material and Methods Molecular karyotyping, utilizing 549,839 single nucleotide polymorphisms (SNPs) with an average spacing of 5.7 kilobases, was performed to screen an initial cohort of 16 EEC patients. Results A de novo microduplication involving chromosomal region 22q11.21 was identified in one CBE patient. Subsequent multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a further 50 EEC cases. One patient with an overlapping 22q11.21 duplication was identified in whom the duplication had been transmitted from the unaffected mother. Conclusions Chromosomal region 22q11 is well known for its susceptibility to genomic rearrangements, and these are associated with various syndromes including the velo-cardio-facial/DiGeorge syndrome (VCFS/DGS), the der(22) syndrome, and the cat-eye syndrome. Duplications in this region result in a wide and variable spectrum of clinical presentations including features of the VCFS/DGS, while some carriers present with a completely normal phenotype.Our findings extent the phenotypic spectrum of the 22q11.2 duplication syndrome, and indicate that this aberration predisposes to CBE with incomplete penetrance.