Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2

Roberto Giorda, Roberto Ciccone, Giorgio Gimelli, Tiziano Pramparo, Silvana Beri, Maria Clara Bonaglia, Sabrina Giglio, Maurizio Genuardi, Jesùs Argente, Mariano Rocchi, Orsetta Zuffardi

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

We describe a new type of rearrangement consisting of the duplication of 8p23.1 and the triplication of 8p23.2 [dup trp(8p)] in two patients affected by mental retardation and minor facial dysmorphisms. Array-comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and genotyping of polymorphic loci allowed us to demonstrate that this rearrangement is mediated by the combined effects of two unrelated low-copy repeats (LCRs). The first set of LCRs consists of the two clusters of olfactory receptor genes (OR-REPs) lying at 8p23.1. The second type of LCRs consists of a 15-kb segmental duplication, lying in inverted orientation at 8p23.2 and enclosing a nonrepeated sequence of approximately 130 kb, named MYOM2-REP because of its proximity to the MYOM2 gene. The molecular characterization of a third case with a dicentric chromosome 8 demonstrated that the rearrangement had been generated by nonallelic homologous recombination between the two MYOM2-REPs. Based on our findings, we propose a model showing that a second recombination event at the level of the OR-REPs leads to the formation of the dup trp(8p) chromosome. This rearrangement can only arise during meiosis in heterozygous carriers of the polymorphic 8p23.1 inversion, whereas in subjects with noninverted chromosomes 8 or homozygous for the inversion only the dicentric chromosome can be formed. Our study demonstrates that nonallelic homologous recombination involving multiple LCRs can generate more complex rearrangements and cause a greater variety of genomic diseases.

Original languageEnglish
Pages (from-to)459-468
Number of pages10
JournalHuman Mutation
Volume28
Issue number5
DOIs
Publication statusPublished - May 2007

Fingerprint

Genomic Segmental Duplications
Chromosomes, Human, Pair 8
Homologous Recombination
Chromosomes
Odorant Receptors
Comparative Genomic Hybridization
Meiosis
Fluorescence In Situ Hybridization
Intellectual Disability
Genetic Recombination
Genes
In Situ Hybridization

Keywords

  • Chromosome 8
  • Chromosome duplication
  • Chromosome triplication
  • Low-copy repeats
  • Nonallelic homologous recombination
  • Recurrent rearrangement

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2. / Giorda, Roberto; Ciccone, Roberto; Gimelli, Giorgio; Pramparo, Tiziano; Beri, Silvana; Bonaglia, Maria Clara; Giglio, Sabrina; Genuardi, Maurizio; Argente, Jesùs; Rocchi, Mariano; Zuffardi, Orsetta.

In: Human Mutation, Vol. 28, No. 5, 05.2007, p. 459-468.

Research output: Contribution to journalArticle

Giorda, R, Ciccone, R, Gimelli, G, Pramparo, T, Beri, S, Bonaglia, MC, Giglio, S, Genuardi, M, Argente, J, Rocchi, M & Zuffardi, O 2007, 'Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2', Human Mutation, vol. 28, no. 5, pp. 459-468. https://doi.org/10.1002/humu.20465
Giorda, Roberto ; Ciccone, Roberto ; Gimelli, Giorgio ; Pramparo, Tiziano ; Beri, Silvana ; Bonaglia, Maria Clara ; Giglio, Sabrina ; Genuardi, Maurizio ; Argente, Jesùs ; Rocchi, Mariano ; Zuffardi, Orsetta. / Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2. In: Human Mutation. 2007 ; Vol. 28, No. 5. pp. 459-468.
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AU - Giorda, Roberto

AU - Ciccone, Roberto

AU - Gimelli, Giorgio

AU - Pramparo, Tiziano

AU - Beri, Silvana

AU - Bonaglia, Maria Clara

AU - Giglio, Sabrina

AU - Genuardi, Maurizio

AU - Argente, Jesùs

AU - Rocchi, Mariano

AU - Zuffardi, Orsetta

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N2 - We describe a new type of rearrangement consisting of the duplication of 8p23.1 and the triplication of 8p23.2 [dup trp(8p)] in two patients affected by mental retardation and minor facial dysmorphisms. Array-comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and genotyping of polymorphic loci allowed us to demonstrate that this rearrangement is mediated by the combined effects of two unrelated low-copy repeats (LCRs). The first set of LCRs consists of the two clusters of olfactory receptor genes (OR-REPs) lying at 8p23.1. The second type of LCRs consists of a 15-kb segmental duplication, lying in inverted orientation at 8p23.2 and enclosing a nonrepeated sequence of approximately 130 kb, named MYOM2-REP because of its proximity to the MYOM2 gene. The molecular characterization of a third case with a dicentric chromosome 8 demonstrated that the rearrangement had been generated by nonallelic homologous recombination between the two MYOM2-REPs. Based on our findings, we propose a model showing that a second recombination event at the level of the OR-REPs leads to the formation of the dup trp(8p) chromosome. This rearrangement can only arise during meiosis in heterozygous carriers of the polymorphic 8p23.1 inversion, whereas in subjects with noninverted chromosomes 8 or homozygous for the inversion only the dicentric chromosome can be formed. Our study demonstrates that nonallelic homologous recombination involving multiple LCRs can generate more complex rearrangements and cause a greater variety of genomic diseases.

AB - We describe a new type of rearrangement consisting of the duplication of 8p23.1 and the triplication of 8p23.2 [dup trp(8p)] in two patients affected by mental retardation and minor facial dysmorphisms. Array-comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and genotyping of polymorphic loci allowed us to demonstrate that this rearrangement is mediated by the combined effects of two unrelated low-copy repeats (LCRs). The first set of LCRs consists of the two clusters of olfactory receptor genes (OR-REPs) lying at 8p23.1. The second type of LCRs consists of a 15-kb segmental duplication, lying in inverted orientation at 8p23.2 and enclosing a nonrepeated sequence of approximately 130 kb, named MYOM2-REP because of its proximity to the MYOM2 gene. The molecular characterization of a third case with a dicentric chromosome 8 demonstrated that the rearrangement had been generated by nonallelic homologous recombination between the two MYOM2-REPs. Based on our findings, we propose a model showing that a second recombination event at the level of the OR-REPs leads to the formation of the dup trp(8p) chromosome. This rearrangement can only arise during meiosis in heterozygous carriers of the polymorphic 8p23.1 inversion, whereas in subjects with noninverted chromosomes 8 or homozygous for the inversion only the dicentric chromosome can be formed. Our study demonstrates that nonallelic homologous recombination involving multiple LCRs can generate more complex rearrangements and cause a greater variety of genomic diseases.

KW - Chromosome 8

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KW - Chromosome triplication

KW - Low-copy repeats

KW - Nonallelic homologous recombination

KW - Recurrent rearrangement

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