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 Ricca; Fabrizia Franchi; Philippos Patsalis; Carolina Sismani; María Angeles Morí; Julián Nevado; Niels Tommerup; Orsetta Zuffardi

doi:10.1007/s00439-018-1941-9

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

^*Corresponding author for this work

9 Citations (Scopus)

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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 language	English
Journal	Human Genetics
Volume	137
Issue number	10
Pages (from-to)	817-829
Number of pages	13
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-018-1941-9
Publication status	Published - 2018

Keywords

Chromothripsis
Meiosis
Mosaicism
Parental origin
Telomere capture
Trisomy rescue

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10.1007/s00439-018-1941-9Licence: CC BY

De novo unbalanced translocations have a complex history/aetiologyFinal published version, 2.01 MBLicence: CC BY

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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

Bonaglia, MC, Kurtas, NE, Errichiello, E, Bertuzzo, S, Beri, S, Mehrjouy, MM, Provenzano, A, Vergani, D, Pecile, V, Novara, F, Reho, P, Di Giacomo, MC, Discepoli, G, Giorda, R, Aldred, MA, Santos-Rebouças, CB, Goncalves, AP, Abuelo, DN, Giglio, S, Ricca, I, Franchi, F, Patsalis, P, Sismani, C, Morí, MA, Nevado, J, Tommerup, N & Zuffardi, O 2018, 'De novo unbalanced translocations have a complex history/aetiology', Human Genetics, vol. 137, no. 10, pp. 817-829. https://doi.org/10.1007/s00439-018-1941-9

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title = "De novo unbalanced translocations have a complex history/aetiology",

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.",

keywords = "Chromothripsis, Meiosis, Mosaicism, Parental origin, Telomere capture, Trisomy rescue",

author = "Bonaglia, {Maria Clara} and Kurtas, {Nehir Edibe} and Edoardo Errichiello and Sara Bertuzzo and Silvana Beri and Mehrjouy, {Mana M.} and Aldesia Provenzano and Debora Vergani and Vanna Pecile and Francesca Novara and Paolo Reho and {Di Giacomo}, {Marilena Carmela} and Giancarlo Discepoli and Roberto Giorda and Aldred, {Micheala A.} and Santos-Rebou{\c c}as, {C{\'i}ntia Barros} and Goncalves, {Andressa Pereira} and Abuelo, {Diane N.} and Sabrina Giglio and Ivana Ricca and Fabrizia Franchi and Philippos Patsalis and Carolina Sismani and Mor{\'i}, {Mar{\'i}a Angeles} and Juli{\'a}n Nevado and Niels Tommerup and Orsetta Zuffardi",

year = "2018",

doi = "10.1007/s00439-018-1941-9",

language = "English",

volume = "137",

pages = "817--829",

journal = "Human Genetics",

issn = "0340-6717",

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TY - JOUR

T1 - De novo unbalanced translocations have a complex history/aetiology

AU - Bonaglia, Maria Clara

AU - Kurtas, Nehir Edibe

AU - Errichiello, Edoardo

AU - Bertuzzo, Sara

AU - Beri, Silvana

AU - Mehrjouy, Mana M.

AU - Provenzano, Aldesia

AU - Vergani, Debora

AU - Pecile, Vanna

AU - Novara, Francesca

AU - Reho, Paolo

AU - Di Giacomo, Marilena Carmela

AU - Discepoli, Giancarlo

AU - Giorda, Roberto

AU - Aldred, Micheala A.

AU - Santos-Rebouças, Cíntia Barros

AU - Goncalves, Andressa Pereira

AU - Abuelo, Diane N.

AU - Giglio, Sabrina

AU - Ricca, Ivana

AU - Franchi, Fabrizia

AU - Patsalis, Philippos

AU - Sismani, Carolina

AU - Morí, María Angeles

AU - Nevado, Julián

AU - Tommerup, Niels

AU - Zuffardi, Orsetta

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Chromothripsis

KW - Meiosis

KW - Mosaicism

KW - Parental origin

KW - Telomere capture

KW - Trisomy rescue

U2 - 10.1007/s00439-018-1941-9

DO - 10.1007/s00439-018-1941-9

M3 - Journal article

C2 - 30276538

AN - SCOPUS:85054311357

SN - 0340-6717

VL - 137

SP - 817

EP - 829

JO - Human Genetics

JF - Human Genetics

IS - 10

ER -

De novo unbalanced translocations have a complex history/aetiology

Abstract

Keywords

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