The position of t(11;22)(q23;q11) constitutional translocation breakpoint is conserved among its carriers

The t(11;22)(q23;q11) translocation is the most common recurrent balanced t ranslocation described in humans. Carriers are phenotypically normal and of ten go undetected until diagnosis as a result of infertility investigations or following the birth of chromosomally unbalanced offspring. Efficient di agnostics of t(11;22) is important for children born to carriers of the tra nslocation and for prenatal and pre-implantation diagnosis. The translocati on breakpoint on chromosome 22 is located within a region containing low co py repeats, and this site is one of the last unfilled gaps in the sequence of this chromosome. This autosome harbors multiple other low copy repeats, which have been entirely sequenced. We report a combined sequencing and fib er FISH breakpoint characterization in five translocation carriers. From on e carrier a cosmid library was constructed, and two chimeric cosmids (cos4_ der11 and cos6_der22) were sequenced, which showed that strong palindromes (or inverted repeats) occur on both chromosomes. The translocation breakpoi nts occur at the tip of both inverted repeats. The palindrome on chromosome s 22 and 11 is composed of 852 and 166 bases, respectively. Four additional carriers were studied using fiber FISH with a resolution limit of 2 kb. An alysis of breakpoints on the DNA sequence level, or at the level of fiber F ISH, indicate that they occur at the same position on both chromosomes in a ll five carriers. Using cos6_der22, PAC 158L19 and BAC 3009A19, we demonstr ate that FISH is an attractive alternative in molecular diagnostics of t(11 ;22), as PCR assays are not reliable, due to the presence of numerous copie s of low copy repeats.