title: High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis.
abstract: Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterised by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): four de novo and three inherited rearrangements not reported among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clinical RSTS phenotype is difficult to assess.
authors.affiliation: Division of Medical Genetics, San Paolo School of Medicine, University of Milan, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.forename: Federica
authors.initials: F
authors.lastname: Mottadelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.forename: Paola
authors.initials: P
authors.lastname: Castronovo
authors.forename: Donatella
authors.initials: D
authors.lastname: Milani
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Bedeschi
authors.forename: Serena
authors.initials: S
authors.lastname: Belli
authors.forename: Alba
authors.initials: A
authors.lastname: Pilotta
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000293:Adolescent; D000328:Adult; D022981:Allelic Imbalance / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D019066:Facies; D005260:Female; D005532:Foot Deformities, Congenital / Q000150:complications / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006228:Hand Deformities, Congenital / Q000150:complications / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D012415:Rubinstein-Taybi Syndrome / Q000150:complications / Q000235:genetics*; D055815:Young Adult
chemical_list: D050882:CREB-Binding Protein; C494363:CREBBP protein, human