Molecular analysis of a reciprocal translocation t(5;11)(q11;p13) in a WAGR patient

Abstract

Most patients with the complex association aniridia - predisposition to Wilms' tumor (WAGR syndrome) present with a de novo constitutional deletion of band 11p13. We report a patient with WAGR syndrome and a reciprocal translocation between chromosomes 5 and 11 t(5;11) (q11;p13). High resolution banding cytogenetic analysis and molecular characterization using 11p13 DNA markers showed a tiny deletion encompassing the gene for CAT but sparing the gene for FSHB. This suggests that syndromes associated with apparently balanced translocations may be due to undetectable loss of material at the breakpoint(s) rather than to breakage in the gene itself.

Fluorescence in situ hybridization characterization of apparently balanced translocation reveals cryptic complex chromosomal rearrangements with unexpected level of complexity

“…3 The risk of phenotypic abnormality associated with de novo balanced translocations is likely to be due to the chance of chromosome breakage disrupting a gene 4 or they may not be truly balanced at the DNA level. 5 Families in which a cytogenetically balanced translocation is present in both a normal and a child with a phenotypic anomaly have been a long-standing puzzle for human geneticists. The conventional wisdom has been that if the same balanced karyotype found in the carrier parent and is also detected at prenatal diagnosis, there is no increased risk for phenotypic abnormality in the child.…”

Detection of deletions in de novo “balanced” chromosome rearrangements: Further evidence for their role in phenotypic abnormalities

“…[3][4][5] A number of hypotheses have been postulated as to the cause of the phenotypic abnormalities. These include (1) a cryptic deletion undetected cytogenetically, causing the loss of a gene or genes, 6,7 (2) a break in a gene at the translocation or inversion breakpoint, leading to loss of function, 8 -10 (3) position effects due to the new cytogenetic rearrangement, 11,12 or (4) uniparental disomy, particularly in chromosomes known to be affected by imprinting. 13,14 In addition, the balanced chromosome rearrangement may be a serendipitous event unrelated to the phenotypic findings in the patient.…”

Identification of a 650 kb duplication at the X chromosome breakpoint in a patient with 46,X,t(X;8)(q28;q12) and non-syndromic mental retardation

“…instances shown deletions or duplications involving megabases of sequence. [8][9][10] Indeed, it is known that approximately 6-10% of apparently balanced de novo translocations are pathogenic 31 32 and a large proportion of these are likely to be unbalanced but cannot be distinguished from true balanced translocations by conventional cytogenetic techniques. 33 Genomic deletions at a breakpoint appear to be more common than duplications.…”

“…26 27 Using fluorescence in situ hybridisation (FISH) with the genomic clones as probes, we identified the X chromosome translocation breakpoint. A series of clones (RP13-156P1, RP5-865E18, RP5-1087L19, RP11-196H18, RP11-115M6, RP1-248B23, RP11-524G17, RP11-296N8, RP11-402H20, and RP11-430K16) were all found to hybridise to the normal X, der(X), and der (8) chromosomes (fig 3). The boundaries of the translocation region were defined using cosmid clone U-58E6 and BAC RP11-405N23, which defined the centromeric and telomeric boundaries respectively.…”

“…However, other mechanisms of disease causation have also been described where (1) a breakpoint disrupts or alters gene expression via a position effect 7 or (2) a cryptic deletion or duplication is identified at the translocation breakpoint. [8][9][10][11] We have investigated a female patient with non-syndromic mental retardation who has inherited an apparently balanced X;autosome translocation, 46,X,t(X;8)(q28;q12)mat. Her mother also had significant intellectual disability from childhood.…”