De novo unbalanced translocations have a complex history/aetiology

Maria Clara Bonaglia, Nehir Edibe Kurtas, Edoardo Errichiello, Sara Bertuzzo, Silvana Beri, Mana M Mehrjouy, Aldesia Provenzano, Debora Vergani, Vanna Pecile, Francesca Novara, Paolo Reho, Marilena Carmela Di Giacomo, Giancarlo Discepoli, Roberto Giorda, Micheala A Aldred, Cíntia Barros Santos-Rebouças, Andressa Pereira Goncalves, Diane N Abuelo, Sabrina Giglio, Ivana RiccaFabrizia Franchi, Philippos Patsalis, Carolina Sismani, María Angeles Morí, Julián Nevado, Niels Tommerup, Orsetta Zuffardi

Research output: Contribution to journalArticle

Abstract

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.

Original languageEnglish
Pages (from-to)817-829
Number of pages13
JournalHuman Genetics
Volume137
Issue number10
DOIs
Publication statusPublished - Oct 2018

    Fingerprint

Keywords

  • DNA End-Joining Repair
  • Female
  • Humans
  • Male
  • Meiosis
  • Recombinational DNA Repair
  • Translocation, Genetic/genetics

Cite this

Bonaglia, M. C., Kurtas, N. E., Errichiello, E., Bertuzzo, S., Beri, S., Mehrjouy, M. M., Provenzano, A., Vergani, D., Pecile, V., Novara, F., Reho, P., Di Giacomo, M. C., Discepoli, G., Giorda, R., Aldred, M. A., Santos-Rebouças, C. B., Goncalves, A. P., Abuelo, D. N., Giglio, S., ... Zuffardi, O. (2018). De novo unbalanced translocations have a complex history/aetiology. Human Genetics, 137(10), 817-829. https://doi.org/10.1007/s00439-018-1941-9