High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis

Cristina Gervasini, Federica Mottadelli, Roberto Ciccone, Paola Castronovo, Donatella Milani, Gioacchino Scarano, Maria Francesca Bedeschi, Serena Belli, Alba Pilotta, Angelo Selicorni, Orsetta Zuffardi, Lidia Larizza

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)768-775
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number7
Publication statusPublished - Jul 2010


  • Array-CGH
  • Differential diagnosis
  • Genomic imbalances
  • Genotype-phenotype correlations
  • Rubinstein-Taybi syndrome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


Dive into the research topics of 'High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis'. Together they form a unique fingerprint.

Cite this