Chromosome 22q11.2 rearrangement disorders

Meiotic unequal crossover events between blocks of low-copy repeats (LCRs) may lead to gene dosage imbalance resulting in genomic disorders. Genomic disorders are frequently associated with mental retardation or learning disabilities and mild to severe congenital anomalies. Chromosome 22q11.2 is particularly susceptible to chromosome rearrangements leading to several genomic disorders including velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS), der(22) syndrome, and cat-eye syndrome (CES), associated with a monosomy, trisomy, and tetrasomy of 22q11.2, respectively. Most VCFS/DGS patients have a similar hemizygous 3-Mb deletion mediated by meiotic interchromosomal homologous recombination events between LCRs termed LCR22s. The reciprocal duplication of the same interval, predicted on expected products of unequal crossover events, results in a more mild condition termed dup(22)(q11.2; q11.2) syndrome. In contrast to VCFS/DGS, dup(22)(q11.2; q11.2) and CES, der(22) syndrome is caused by a different molecular mechanism. Der(22) disorder arises in offspring of normal carriers of the constitutional t(1 1;22) (q23.3; q1 1.2) translocation by recombination between AT-rich (high AT sequence composition) palindromic sequences on 1 1q23.3 and 22q1 1.2. The palindromic sequence on 22q1 1.2 is within one of the LCR22s. Interestingly, both recurrent and novel breakpoints occur most often in LCR22s, making them an important architectural feature associated with susceptibility to genome rearrangements. To gain further insight into the mechanisms of how the LCR22s are involved in chromosome rearrangements, efforts are underway to determine the molecular evolution, structure, size, orientation, and their level of variability in humans.