[Show abstract][Hide abstract] ABSTRACT: In about one third of healthy subjects, the microscopic analysis of chromosomes reveals heteromorphisms with no clinical implications: for example changes in size of the short arm of acrocentric chromosomes. In patients with a pathological phenotype, however, a large acrocentric short arm can mask a genomic imbalance and should be investigated in more detail. We report the first case of a chromosome 22 with a large acrocentric short arm masking a partial trisomy of the distal long arm, characterized by SNP array. We suggest a possible molecular mechanism underlying the rearrangement.
We report the case of a 15-year-old dysmorphic girl with low grade psychomotor retardation characterized by a karyotype with a large acrocentric short arm of one chromosome 22. Cytogenetic analysis revealed a normal karyotype with a very intense Q-fluorescent and large satellite on the chromosome 22 short arm. Fluorescence in situ hybridisation analysis showed a de novo partial trisomy of the 22q13.2-qter chromosome region attached to the short arm of chromosome 22. SNP-array analysis showed that the duplication was 8.5 Mb long and originated from the paternal chromosome. Haplotype analysis revealed that the two paternal copies of the distal part of chromosome 22 have the same haplotype and, therefore, both originated from the same paternal chromosome 22. A possible molecular mechanism that could explain this scenario is a break-induced replication (BIR) which is involved in non-reciprocal translocation events.
The combined use of FISH and SNP arrays was crucial for a better understanding of the molecular mechanism underlying this rearrangement. This strategy could be applied for a better understanding of the molecular mechanisms underlying cryptic chromosomal rearrangements.
BMC Medical Genetics 07/2015; 16(1):47. DOI:10.1186/s12881-015-0193-y · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe a premature newborn child with left renal agenesis, right low functional kidney, altered chemical-clinical parameters, neutropenia, recurrent pulmonary infections, long bone diaphysis broadening, growth and developmental delay. Postnatal cytogenetic analysis revealed a 46,XY,t(2;7)(p13;p12) de-novo karyotype. The chromosome breakpoints were defined by FISH using BAC probes and initially restricted to about 123,000bp in 2p13 and delimited to 84,600bp in 7p12. Bioinformatic analysis of these genomic regions showed two genes that are involved in the rearrangement: exocyst C6B (EXOC6B) for chromosome 2 breakpoint and tensin3 (TNS3) for chromosome 7 breakpoint. A EXOC6B-TNS3 fusion transcript together with a reciprocal TNS3-EXOC6B chimeric RNA have been detected by RT-PCR performed on skin fibroblasts RNA of the proband. These data localize the chromosome 2 breakpoint within the first intron of EXOC6B, while the translocation event on chromosome 7 occurred in intron 15 of TNS3. We hypothesize that the phenotype observed in the patient results from one or several mechanisms including: haploinsufficiency of EXOC6B and TNS3 genes; a dominant negative effect exerted by the chimeric transcripts; a disregulation in the expression of other genes adjacent the breakpoints. Although no clear evidences exist supporting a role of any of the above mentioned mechanisms in the pathogenesis of the complex phenotype, immunofluorescence analysis of tensin1 in the patient's fibroblasts suggests that the TNS3 gene haploinsufficiency results in a reduced expression of tensin1. These cells may be therefore a model for understanding the role and the organization of the tensin protein family.
European Journal of Medical Genetics 04/2008; 51(4):292-302. DOI:10.1016/j.ejmg.2008.02.006 · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interstitial deletions and pericentric inversions of chromosome 4 appear to be unusual phenomena. Here, we report the case of a 14-year-old boy with severe psychomotor retardation with a de novo 46,XY,der(4)del(p15.2p15.31)inv(4)(p15.2q13.3)del(4)(q13.2q13.2) karyotype. We used FISH analysis with YAC and BAC clones to characterise the inversion's breakpoints. A complex event with six breakpoints was found, characterised by a pericentric inversion and two deletions, the first on the short arm of chromosome 4 (4p) and the second on the long arm of chromosome 4 (4q). The deletion events had removed two segments, one of approximately 5 Mb, from 4p, outside the inversion, and the other 2 Mb from 4q, inside the inversion. These rearrangements were not found in the parents. Microsatellite marker analysis showed that the inversion carrying chromosome 4 was derived from the father. Bioinformatic analysis of the human genome sequence allowed us to identify several hemizygotic genes in the patient, which might be involved in the pathogenesis of this clinical phenotype.
European Journal of Medical Genetics 05/2006; 49(3):215-23. DOI:10.1016/j.ejmg.2005.07.004 · 1.47 Impact Factor