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.

A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology

“…These results demonstrate that apparently balanced translocations might not be balanced at the DNA level. The development of new technologies such as array CGH and SNP arrays has already started to reveal the complex nature of apparently balanced translocations (Gribble et al, 2005;De Gregori et al, 2007;Baptista et al, 2008;Fantes et al, 2008). Even though the deleted region seen in case 3 overlaps with several genomic variants reported in controls in the Database of Genomic Variants the combination of this deletion with the translocation may be involved in the patient's phenotype.…”

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of <i>LRFN5</i> Expression

“…Alternatively, since a centromere is likely to associate with heterochromatin at the nuclear periphery, i.e. in a region of low gene expression [Wiblin et al, 2005], this could have displaced LRFN5 to a region within the nucleus where gene expression was less favoured, and dysregulation could occur, especially since LRFN5 is within the 14q21.2 R-sub-band [Fantes et al, 2008].…”

“…like the 14; 18 translocation increasing MYC expression in acute lymphoblastic leukaemia), by disrupting distal regulatory elements that even may reside within neighbouring genes [Kleinjan and van Heyningen, 2005], or by displacing genes within the nucleus to an environment less favourable for transcription [Cremer and Cremer, 2001]. Translocations affecting R-positive bands (light bands on G-banded karyotypes) are more likely to associate with an abnormal phenotype than translocations through Gpositive bands, usually regardless of a gene being disrupted or not [Fantes et al, 2008]. This suggests that the genomic context of the breakpoint has prognostic significance.…”

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes

“…Historically, FISH analysis using tiling BAC clones within the predicted translocation junction chromosome bands has been used to identify the clone that spans the breakpoint region. Currently, the focus of most of the studies investigating reciprocal translocation breakpoints utilizes array technology to determine whether an apparent balanced translocation by GTG banding analysis is indeed balanced (De Gregori et al 2007;Fantes et al 2008;Schluth-Bolard et al 2009) rather than breakpoint identification per se.…”