Breakpoint Mapping and Array CGH in Translocations: Comparison of a Phenotypically Normal and an Abnormal Cohort

Abstract

We report the analyses of breakpoints in 31 phenotypically normal and 14 abnormal carriers of balanced translocations. Our study assesses the differences between balanced translocations in normal carriers and those in abnormal carriers, focusing on the presence of genomic imbalances at the breakpoints or elsewhere in the genome, presence of cryptic chromosome rearrangements, and gene disruption. Our hypothesis is that all four features will be associated with phenotypic abnormalities and absent or much less frequent in a normal population. In the normal cohort, we identified neither genomic imbalances at the breakpoints or elsewhere in the genome nor cryptic chromosome rearrangements. In contrast, we identified candidate disease-causing imbalances in 4/14 abnormal patients. These were three breakpoint associated deletions and three deletions unrelated to the breakpoints. All six de novo deletions originated on the paternally inherited chromosome. Additional complexity was also present in one of these cases. Gene disruption by the breakpoints was present in 16/31 phenotypically normal individuals and in 5/14 phenotypically abnormal patients. Our results show that translocations in phenotypically abnormal patients are molecularly distinct from those in normal individuals: the former are more likely to be associated with genomic imbalances at the breakpoints or elsewhere and with chromosomal complexity, whereas the frequency of gene disruption is similar in both normal and abnormal translocation carriers.

Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients

“…For example, the IL1RAPL1 gene has been implicated in monogenic forms of intellectual disability and autism in several unrelated patients, and recent characterisation of the IL1RAPL1 knockout mouse illuminated disease-associated alterations in the JNK signalling cascade (Pavlowsky et al 2010a, b). These studies, paralleled by our identification of a de novo MAPK10/JNK3 (OMIM 602897) truncation mutation in a patient with a severe neurodevelopmental disorder (Shoichet et al 2006), and the fact that this gene is among those affected by a rearrangement in another patient with a complex physical and cognitive disorder (Baptista et al 2008), make clear that JNKs-in particular the CNS-expressed MAPK10/ JNK3-are candidates for mutation identification in patients with early-onset neurological disorders. Here, we describe the clinical and genetic characterisation of an unrelated patient with a cognitive phenotype harbouring a de novo chromosome rearrangement affecting the MAPK10/JNK3 gene.…”

“…sub-resolution copy number variations on other chromosomes or polymorphic disease susceptibility variants in other genes) that might contribute to the more severe phenotype in Patient 1. Within this context, it is interesting that a third ID patient with a chromosome rearrangement involving the MAPK10/JNK3 gene has been described (Baptista et al 2008). This patient has a complex rearrangement that is accompanied by a deletion affecting six genes, some of which may contribute to the complex phenotype, which includes respiratory problems and scoliosis in addition to learning deficits.…”

Unexpected complexity at breakpoint junctions in phenotypically normal individuals and mechanisms involved in generating balanced translocations t(1;22)(p36;q13)

“…Although we found some similar events across the t(1;22) cases, the complexity at the breakpoint junctions exceeded our expectations given that these subjects are phenotypically normal. Recent reports have suggested the translocation breakpoints in phenotypically normal individuals are relatively simple and not associated with genomic imbalances (Baptista et al 2005(Baptista et al , 2008. However, these studies have examined the translocation breakpoints at the resolution of fosmid clones (∼40 kb) or PCR products (∼10 kb).…”

Advanced age increases chromosome structural abnormalities in human spermatozoa

“…8 Similarly, all de novo deletions described by aCGH in carriers of balanced translocations and abnormal phenotype turned out to be of paternal origin. 9 Moreover, studies on the origin of the recurrent de novo t (11;22) found that it was paternal in 100% of cases 10,11 and Thomas et al 12 confirmed a paternal origin of non-recurrent de novo balanced reciprocal translocations in 96% of cases.…”