Narrowing the chromosome 22q11.2 locus duplicated in bladder exstrophy-epispadias complex

Objectives. To refine the chromosome 22q11.2 locus duplicated in some individuals with the congenital malformation called bladder exstrophy-epispadias complex (BEEC), and to determine whether the encompassed genes are expressed in normal developing and mature human urinary bladders.
Subjects and methods. Genomic copy number analyses of human leucocyte DNA from individuals with the commonest form of BEEC, classical bladder exstrophy (CBE), quantitative polymerase chain reaction of embryonic human bladders, and interrogation of single cell RNA sequencing of the adult human bladder.
Results. Using DNA from an individual with CBE, the 22q11.2 duplicated locus was refined by identification of a maternally inherited 314 kb duplication (chr22:21,147,293-21,461,017). The eight protein coding genes (AIFM3, CRKL, LZTR1, PI4KA, P2RX6, SLC7A4, SNAP29 and THAP7) within the locus were expressed in normal developing and mature bladders. To determine whether duplications in any of these individual genes were associated with CBE, we undertook copy number analyses in 115 individuals with CBE without duplications of the whole locus. No duplications of individual genes were found.
Conclusion. The study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes within this locus are expressed in human bladders. The fact that individuals with CBE without duplications of the whole locus also lacked duplication of any of the individual genes suggests that in individuals with a 22q11 duplication the pathogenesis of the malformation requires duplication, and hence postulated overexpression during organogenesis, of multiple genes within the locus.