High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints

Cristina Gervasini, Paola Castronovo, Angela Bentivegna, Federica Mottadelli, Francesca Faravelli, Maria Luisa Giovannucci-Uzielli, Alice Pessagno, Emanuela Lucci-Cordisco, Anna Maria Pinto, Leonardo Salviati, Angelo Selicorni, Romano Tenconi, Giovanni Neri, Lidia Larizza

Research output: Contribution to journalArticle

Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5-10 kb. Four of our five intragenic breakpoints cluster at the 5′ end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region's vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS.

Original languageEnglish
Pages (from-to)567-573
Number of pages7
JournalGenomics
Volume90
Issue number5
DOIs
Publication statusPublished - Nov 2007

Fingerprint

Rubinstein-Taybi Syndrome
Germ Cells
Mutation
Genomic Segmental Duplications
Interspersed Repetitive Sequences
Nucleic Acid Repetitive Sequences
Gene Deletion
Microsatellite Repeats
Genes
Exons
Clone Cells
Genome
Neoplasms

Keywords

  • Breakpoint mapping
  • Microdeletion
  • Mosaicism
  • Rubinstein-Taybi syndrome

ASJC Scopus subject areas

  • Genetics

Cite this

Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., ... Larizza, L. (2007). High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. Genomics, 90(5), 567-573. https://doi.org/10.1016/j.ygeno.2007.07.012

High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. / Gervasini, Cristina; Castronovo, Paola; Bentivegna, Angela; Mottadelli, Federica; Faravelli, Francesca; Giovannucci-Uzielli, Maria Luisa; Pessagno, Alice; Lucci-Cordisco, Emanuela; Pinto, Anna Maria; Salviati, Leonardo; Selicorni, Angelo; Tenconi, Romano; Neri, Giovanni; Larizza, Lidia.

In: Genomics, Vol. 90, No. 5, 11.2007, p. 567-573.

Research output: Contribution to journalArticle

Gervasini, C, Castronovo, P, Bentivegna, A, Mottadelli, F, Faravelli, F, Giovannucci-Uzielli, ML, Pessagno, A, Lucci-Cordisco, E, Pinto, AM, Salviati, L, Selicorni, A, Tenconi, R, Neri, G & Larizza, L 2007, 'High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints', Genomics, vol. 90, no. 5, pp. 567-573. https://doi.org/10.1016/j.ygeno.2007.07.012
Gervasini C, Castronovo P, Bentivegna A, Mottadelli F, Faravelli F, Giovannucci-Uzielli ML et al. High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. Genomics. 2007 Nov;90(5):567-573. https://doi.org/10.1016/j.ygeno.2007.07.012
Gervasini, Cristina ; Castronovo, Paola ; Bentivegna, Angela ; Mottadelli, Federica ; Faravelli, Francesca ; Giovannucci-Uzielli, Maria Luisa ; Pessagno, Alice ; Lucci-Cordisco, Emanuela ; Pinto, Anna Maria ; Salviati, Leonardo ; Selicorni, Angelo ; Tenconi, Romano ; Neri, Giovanni ; Larizza, Lidia. / High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. In: Genomics. 2007 ; Vol. 90, No. 5. pp. 567-573.
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AU - Mottadelli, Federica

AU - Faravelli, Francesca

AU - Giovannucci-Uzielli, Maria Luisa

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AU - Pinto, Anna Maria

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N2 - Rubinstein-Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5-10 kb. Four of our five intragenic breakpoints cluster at the 5′ end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region's vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS.

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