ORIGINAL ARTICLE

Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation

Elyes Chabchoub¹, Laura Rodríguez², Enrique Galán³, Elena Mansilla², Maria Luisa Martínez-Fernandez², Maria Luisa Martínez-Frías², Jean-Pierre Fryns¹, Joris Robert Vermeesch¹

¹ Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
² Estudio Colaborativo Español de Malformaciones Congénitas del Centro de Investigación sobre Anomalías Congénitas, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain
³ Servicio de Pediatría. Hospital Materno Infantil de la seguridad Social de Badajoz, Badajoz, Spain

Correspondence to:
J R Vermeesch
Center for Human Genetics, Herestraat 49,3000 Leuven, Belgium; Joris.Vermeesch{at}uz.kuleuven.ac.be

Background: Broken chromosomes must acquire new telomeric "caps" to be structurally stable. Chromosome healing can be mediated either by telomerase through neo-telomere synthesis or by telomere capture.

Aim: To unravel the mechanism(s) generating complex chromosomal mosaicisms and healing broken chromosomes.

Methods: G banding, array comparative genomic hybridization (aCGH), fluorescence in-situ hybridisation (FISH) and short tandem repeat analysis (STR) was performed on a girl presenting with mental retardation, facial dysmorphism, urogenital malformations and limb anomalies carrying a complex chromosomal mosaicism.

Results & discussion: The karyotype showed a de novo chromosome rearrangement with two cell lines: one cell line with a deletion 9pter and one cell line carrying an inverted duplication 9p and a non-reciprocal translocation 5pter fragment. aCGH, FISH and STR analysis enabled the deduction of the most likely sequence of events generating this complex mosaic. During embryogenesis, a double-strand break occurred on the paternal chromosome 9. Following mitotic separation of both broken sister chromatids, one acquired a telomere vianeo-telomere formation, while the other generated a dicentric chromosome which underwent breakage during anaphase, giving rise to the del inv dup(9) that was subsequently healed by chromosome 5 telomere capture.

Conclusion: Broken chromosomes can coincidently be rescued by both telomere capture and neo-telomere synthesis.

Abbreviations: aCGH, array comparative genomic hybridisation; BLAST, basic local alignment search tool; DSB, double-strand break; FISH, fluorescence in situ hybridization; LCRs, low-copy repeats

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