Molecular and genomic characterisation of cryptic chromosomal alterations leading to paternal duplication of the 11p15.5 Beckwith-Wiedemann region.

S. Russo, P. Finelli, M. P. Recalcati, S. Ferraiuolo, F. Cogliati, B. Dalla Bernardina, M. G. Tibiletti, M. Agosti, M. Sala, M. T. Bonati, L. Larizza

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Abstract

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of paediatric tumours. The aetiology involves epigenetic and genetic alterations affecting the 11p15 region, methylation of the differentially methylated DMR2 region being the most common defect, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of DMR1. A few patients have cytogenetic abnormalities involving 11p15.5. METHODS: Screening of 70 trios of BWS probands for 11p mosaic paternal UPD and for cryptic cytogenetic rearrangements using microsatellite segregation analysis identified a profile compatible with paternal 11p15 duplication in two patients. RESULTS: Fluorescence in situ hybridisation analysis revealed in one case the unbalanced translocation der(21)t(11;21)(p15.4;q22.3) originated from missegregation of a cryptic paternal balanced translocation. The second patient, trisomic for D11S1318, carried a small de novo dup(11)(p15.5p15.5), resulting from unequal recombination at paternal meiosis I. The duplicated region involves only IC1 and spares IC2/LIT1, as shown by fluorescent in situ hybridisation (FISH) mapping of the proximal duplication breakpoint within the amino-terminal part of KvLQT1. CONCLUSIONS: An additional patient with Wolf-Hirschorn syndrome was shown by FISH studies to carry a der(4)t(4;11)(p16.3;p15.4), contributed by a balanced translocation father. Interestingly, refined breakpoint mapping on 11p and the critical regions on the partner 21q and 4p chromosomal regions suggested that both translocations affecting 11p15.4 are mediated by segmental duplications. These findings of chromosomal rearrangements affecting 11p15.5-15.4 provide a tool to further dissect the genomics of the BWS region and the pathogenesis of this imprinting disorder.

Original languageEnglish
JournalJournal of Medical Genetics
Volume43
Issue number8
DOIs
Publication statusPublished - Aug 2006

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Beckwith-Wiedemann Syndrome
Fluorescence In Situ Hybridization
Wolf-Hirschhorn Syndrome
Genomic Segmental Duplications
Uniparental Disomy
Meiosis
Genomics
Epigenomics
Cytogenetics
Fathers
Chromosome Aberrations
Microsatellite Repeats
Methylation
Genetic Recombination
Pediatrics
Mutation
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

@article{a2ffa59afe2c490680a301caeed8d0bc,
title = "Molecular and genomic characterisation of cryptic chromosomal alterations leading to paternal duplication of the 11p15.5 Beckwith-Wiedemann region.",
abstract = "BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of paediatric tumours. The aetiology involves epigenetic and genetic alterations affecting the 11p15 region, methylation of the differentially methylated DMR2 region being the most common defect, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of DMR1. A few patients have cytogenetic abnormalities involving 11p15.5. METHODS: Screening of 70 trios of BWS probands for 11p mosaic paternal UPD and for cryptic cytogenetic rearrangements using microsatellite segregation analysis identified a profile compatible with paternal 11p15 duplication in two patients. RESULTS: Fluorescence in situ hybridisation analysis revealed in one case the unbalanced translocation der(21)t(11;21)(p15.4;q22.3) originated from missegregation of a cryptic paternal balanced translocation. The second patient, trisomic for D11S1318, carried a small de novo dup(11)(p15.5p15.5), resulting from unequal recombination at paternal meiosis I. The duplicated region involves only IC1 and spares IC2/LIT1, as shown by fluorescent in situ hybridisation (FISH) mapping of the proximal duplication breakpoint within the amino-terminal part of KvLQT1. CONCLUSIONS: An additional patient with Wolf-Hirschorn syndrome was shown by FISH studies to carry a der(4)t(4;11)(p16.3;p15.4), contributed by a balanced translocation father. Interestingly, refined breakpoint mapping on 11p and the critical regions on the partner 21q and 4p chromosomal regions suggested that both translocations affecting 11p15.4 are mediated by segmental duplications. These findings of chromosomal rearrangements affecting 11p15.5-15.4 provide a tool to further dissect the genomics of the BWS region and the pathogenesis of this imprinting disorder.",
author = "S. Russo and P. Finelli and Recalcati, {M. P.} and S. Ferraiuolo and F. Cogliati and {Dalla Bernardina}, B. and Tibiletti, {M. G.} and M. Agosti and M. Sala and Bonati, {M. T.} and L. Larizza",
year = "2006",
month = "8",
doi = "10.1136/jmg.2005.038398",
language = "English",
volume = "43",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "8",

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TY - JOUR

T1 - Molecular and genomic characterisation of cryptic chromosomal alterations leading to paternal duplication of the 11p15.5 Beckwith-Wiedemann region.

AU - Russo, S.

AU - Finelli, P.

AU - Recalcati, M. P.

AU - Ferraiuolo, S.

AU - Cogliati, F.

AU - Dalla Bernardina, B.

AU - Tibiletti, M. G.

AU - Agosti, M.

AU - Sala, M.

AU - Bonati, M. T.

AU - Larizza, L.

PY - 2006/8

Y1 - 2006/8

N2 - BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of paediatric tumours. The aetiology involves epigenetic and genetic alterations affecting the 11p15 region, methylation of the differentially methylated DMR2 region being the most common defect, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of DMR1. A few patients have cytogenetic abnormalities involving 11p15.5. METHODS: Screening of 70 trios of BWS probands for 11p mosaic paternal UPD and for cryptic cytogenetic rearrangements using microsatellite segregation analysis identified a profile compatible with paternal 11p15 duplication in two patients. RESULTS: Fluorescence in situ hybridisation analysis revealed in one case the unbalanced translocation der(21)t(11;21)(p15.4;q22.3) originated from missegregation of a cryptic paternal balanced translocation. The second patient, trisomic for D11S1318, carried a small de novo dup(11)(p15.5p15.5), resulting from unequal recombination at paternal meiosis I. The duplicated region involves only IC1 and spares IC2/LIT1, as shown by fluorescent in situ hybridisation (FISH) mapping of the proximal duplication breakpoint within the amino-terminal part of KvLQT1. CONCLUSIONS: An additional patient with Wolf-Hirschorn syndrome was shown by FISH studies to carry a der(4)t(4;11)(p16.3;p15.4), contributed by a balanced translocation father. Interestingly, refined breakpoint mapping on 11p and the critical regions on the partner 21q and 4p chromosomal regions suggested that both translocations affecting 11p15.4 are mediated by segmental duplications. These findings of chromosomal rearrangements affecting 11p15.5-15.4 provide a tool to further dissect the genomics of the BWS region and the pathogenesis of this imprinting disorder.

AB - BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of paediatric tumours. The aetiology involves epigenetic and genetic alterations affecting the 11p15 region, methylation of the differentially methylated DMR2 region being the most common defect, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of DMR1. A few patients have cytogenetic abnormalities involving 11p15.5. METHODS: Screening of 70 trios of BWS probands for 11p mosaic paternal UPD and for cryptic cytogenetic rearrangements using microsatellite segregation analysis identified a profile compatible with paternal 11p15 duplication in two patients. RESULTS: Fluorescence in situ hybridisation analysis revealed in one case the unbalanced translocation der(21)t(11;21)(p15.4;q22.3) originated from missegregation of a cryptic paternal balanced translocation. The second patient, trisomic for D11S1318, carried a small de novo dup(11)(p15.5p15.5), resulting from unequal recombination at paternal meiosis I. The duplicated region involves only IC1 and spares IC2/LIT1, as shown by fluorescent in situ hybridisation (FISH) mapping of the proximal duplication breakpoint within the amino-terminal part of KvLQT1. CONCLUSIONS: An additional patient with Wolf-Hirschorn syndrome was shown by FISH studies to carry a der(4)t(4;11)(p16.3;p15.4), contributed by a balanced translocation father. Interestingly, refined breakpoint mapping on 11p and the critical regions on the partner 21q and 4p chromosomal regions suggested that both translocations affecting 11p15.4 are mediated by segmental duplications. These findings of chromosomal rearrangements affecting 11p15.5-15.4 provide a tool to further dissect the genomics of the BWS region and the pathogenesis of this imprinting disorder.

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