FISH mapping of de novo apparently balanced chromosome rearrangements identifies characteristics associated with phenotypic abnormality

Abstract

We report fluorescence in situ hybridization (FISH) mapping of 152, mostly de novo, apparently balanced chromosomal rearrangement (ABCR) breakpoints in 76 individuals, 30 of whom had no obvious phenotypic abnormality (control group) and 46 of whom had an associated disease (case group). The aim of this study was to identify breakpoint characteristics that could discriminate between these groups and which might be of predictive value in de novo ABCR (DN-ABCR) cases detected antenatally. We found no difference in the proportion of breakpoints that interrupted a gene, although in three cases, direct interruption or deletion of known autosomal-dominant or X-linked recessive Mendelian disease genes was diagnostic. The only significant predictor of phenotypic abnormality in the group as a whole was the localization of one or both breakpoints to an R-positive (G-negative) band with estimated predictive values of 0.69 (95% CL 0.54-0.81) and 0.90 (95% CL 0.60-0.98), respectively. R-positive bands are known to contain more genes and have a higher guanine-cytosine (GC) content than do G-positive (R-negative) bands; however, whether a gene was interrupted by the breakpoint or the GC content in the 200 kB around the breakpoint had no discriminant ability. Our results suggest that the large-scale genomic context of the breakpoint has prognostic utility and that the pathological mechanism of mapping to an R-band cannot be accounted for by direct gene inactivation.

Figure 1

Breakpoint Distribution The genome-wide distribution of the 152 breakpoints mapped in this study. The breakpoints in cases are shown as red arrowheads on the right-hand side of each ideogram, and the breakpoints in controls are shown as blue arrowheads on the left-hand side. This figure was made with the Karyoview facility on the Ensembl Genome Browser.

Figure 2

Band-Type Distribution Graphical representations of the cytogenetic band distribution of the molecularly characterized breakpoints. The left-hand bar diagram shows the distribution in the Case group, and the right-hand diagram shows the Control-group distribution. R indicates R+ve bands (taken to be synonymous with G-light bands here). Cen or R/G indicates bands assigned as centromeric or existing at the junction between an R+ve band and a G+ve band. G1–G4 indicate G-dark bands, with G1 the darkest and G4 the lightest.