title: High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.
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.
authors.affiliation: Division of Medical Genetics, San Paolo School of Medicine, University of Milan, 20142 Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.forename: Paola
authors.initials: P
authors.lastname: Castronovo
authors.forename: Angela
authors.initials: A
authors.lastname: Bentivegna
authors.forename: Federica
authors.initials: F
authors.lastname: Mottadelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Faravelli
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Giovannucci-Uzielli
authors.forename: Alice
authors.initials: A
authors.lastname: Pessagno
authors.forename: Emanuela
authors.initials: E
authors.lastname: Lucci-Cordisco
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pinto
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Romano
authors.initials: R
authors.lastname: Tenconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000328:Adult; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D005854:Germ Cells / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D012415:Rubinstein-Taybi Syndrome / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D050882:CREB-Binding Protein; C494363:CREBBP protein, human