Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11;22) families

Abstract

The t(11;22) is the only known recurrent, non-Robertsonian constitutional translocation. We have analyzed t(11;22) balanced-translocation carriers from multiple unrelated families by FISH, to localize the t(11;22) breakpoints on both chromosome 11 and chromosome 22. In 23 unrelated balanced-translocation carriers, the breakpoint was localized within a 400-kb interval between D22S788 (N41) and ZNF74, on 22q11. Also, 13 of these 23 carriers were tested with probes from chromosome 11, and, in each, the breakpoint was localized between D11S1340 and APOA1, on 11q23, to a region </=185 kb. Thus, the breakpoints on both chromosome 11 and chromosome 22 are clustered in multiple unrelated families. Supernumerary-der(22)t(11;22) syndrome can occur in the progeny of balanced-t(11;22) carriers, because of malsegregation of the der(22). There has been speculation regarding the mechanism by which the malsegregation occurs. To elucidate this mechanism, we have analyzed 16 of the t(11;22) families, using short tandem-repeat-polymorphism markers on both chromosome 11 and chromosome 22. In all informative cases the proband received two of three alleles, for markers above the breakpoint on chromosome 22 and below the breakpoint on chromosome 11, from the t(11;22)-carrier parent. These data strongly suggest that 3:1 meiosis I malsegregation in the t(11;22) balanced-translocation-carrier parent is the mechanism in all 16 families. Taken together, these results establish that the majority of t(11;22) translocations occur within the same genomic intervals and that the majority of supernumerary-der(22) offspring result from a 3:1 meiosis I malsegregation in the balanced-translocation carrier.

Figure 1

Location of t(11;22) breakpoint. Chromosomes are illustrated as thick horizontal lines with arrowheads at both ends. The orientation of the centromere (Cen) and telomere (Tel) are also indicated. The t(11;22) breakpoint is denoted by a zigzag line. STS markers used for genotype analysis are indicated by an asterisk (*). A, 22q11.2. Clones used to construct a map in the t(11;22) breakpoint region are indicated by thin lines. The location of cosmids used as FISH probes—c68a1 and c87f9—are shown as thick lines. B, 11q22-q23. FISH probe BAC 442e11 is shown as a thick line.

Figure 2

FISH analysis I. A, B, and D, Metaphase chromosomes derived from a balanced-t(11;22) carrier hybridized to different test probes—c68a1 (A), c87f9 (B), and BAC 442e11 (D). In each case, the control probe that marks the telomeric end of chromosome 22 is seen as a red signal (rhodamine), and test probes are seen as a green signal (fluorescein). Chromosomes with fluorescent signal are indicated by arrows and are labeled. C, Interphase nucleus hybridized to FISH probe BAC 442e11. Two discrete signals indicate that the clone BAC 442e11 does not contain chromosome 11–specific duplications.

Figure 3

FISH analysis II. A, Metaphase chromosomes derived from a balanced-t(11;22) carrier hybridized to test probe PAC 181g22 seen as a red signal (rhodamine). B, DAPI-counterstained image in A, inverted to gray scale. Chromosomes with fluorescent signal are indicated by arrows and are labeled. C, Interphase nucleus hybridized to FISH probe BAC 48m11 seen as multiple red signals (rhodamine), indicating chromosome 22–specific duplicated sequences. The green signal (fluorescein) is from probe c16e8, a unique chromosome 22 cosmid probe containing marker D22S66 (ph 160b), which maps between markers D22S944 and 115STS (see fig. 1A) within the 22q11.2 deletion.