Mechanisms of germline translocations in chromosome 22q11

Abstract

Chromosomal abnormalities are found in nearly 1% of newborns each year. The chromosome 22q11 region is susceptible to rearrangements resulting in congenital anomaly disorders due to altered gene copy number. Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with a 3 Mb deletion in the 22q11 region while cat-eye syndrome (CES) and der(22) syndrome are associated with duplications of the 22q11 region. Low copy repeats on chromosome 22 (LCR22s) coincide with the breakpoint regions of VCFS/DGS and CES which mediate homologous recombination events leading to the rearrangements. Der(22) syndrome occurs in offspring of carriers of the recurrent constitutional t(11;22) due to 3:1 meiotic non-disjunction events. The constitutional t(11;22) translocation disrupts one particular LCR22 but the mechanism underlying the rearrangement had been elusive. In order to better understand the mechanism associated with the constitutional t(11;22) translocation, we cloned the breakpoint junction of the der(11) and der(22) chromosomes. The constitutional t(11;22) breakpoint occurred in AT-rich palindromes on both chromosomes 11 and 22 resulting in deletions in the center of the palindrome. We hypothesized that these palindromes form stem-loop structures which result in their sensitivity to double-stranded breaks promoting recombination in the region.;In order to better understand the mechanism of non-recurrent translocations in the chromosome 22q11 region and to determine whether the mechanism is the same as found for the constitutional t(11;22) translocation, fourteen patients with non recurrent translocations involving the chromosome 22q11 region were studied. Of the non-recurrent translocations studied, five were found to cluster in the same LCR22 as for the t(11;22) breakpoint and are likely to be mediated by the same mechanism. Of the remaining translocations breakpoints four occurred in other LCR22s or LCR22 sequences while six derivative chromosomes had unique breakpoints across the 22q11 region, with the majority being located in the VCFS/DGS deletion region. Interestingly, the breakpoints of the partner chromosomes of these non-recurrent translocations were all located in the telomeric band of the chromosome, regions also prone to chromosomal breaks. The telomeric band of the chromosome from centromere to telomere begins with unique chromosome specific sequence. This region is followed by telomere associated repeats which are sequences repeated in a mosaic pattern on different but not all chromosomes. The last region of the chromosome are repeats of TTAGGGn for 3 to 20 Kb. We examined the region of chromosomal breakage on the partner chromosome and determined that six translocations had breakpoints in the TAR or TTAGGGn regions in the telomere with the remaining in more centromeric unique nearby sequences. We hypothesized that these translocations are a result of double strand break repair in the cell, where the broken ends of the telomere regions are brought together with the broken ends of the 22q11 regions resulting in translocated chromosomes.