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.

Protein Lysine Acetylation by p300/CBP

“…40% of RTS patients either have unknown RTS etiology, or may be more appropriately diagnosed with a different (but phenotypically similar) syndrome, such as Saethre–Chotzen syndrome (caused by mutations in TWIST1) or Mowat–Wilson syndrome (caused by mutations in ZEB2). 375 Approximately 55% of RTS patients have germline mutations in CBP, and approximately 5% of RTS patients have germline mutations in p300. 374 RTS patients with p300 mutations often have milder phenotypes than those with CBP mutations.…”

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

“…The authors hypothesized that if the haploinsufficiency of RNF135 could contribute to an overgrowth syndrome, then duplication of RNF135 could contribute to the skeletal anomalies and ID seen in their patient. 38 However, it is also possible that Rubinstein-Taybi syndrome could be unrelated to the microduplication in this family and may be attributable to an unidentified mutation, such as one in EP300, which was not sequenced in this proband.…”

“…An NF1-REP A to NF1-REP B microduplication has been described in a patient with a clinical diagnosis of Rubinstein-Taybi syndrome and his healthy sister. 38 Growth parameters were not available for this family, although growth retardation is a feature of Rubinstein-Taybi syndrome. The authors hypothesized that if the haploinsufficiency of RNF135 could contribute to an overgrowth syndrome, then duplication of RNF135 could contribute to the skeletal anomalies and ID seen in their patient.…”

Rubinstein–Taybi syndrome: New neuroradiological and neuropsychiatric insights from a multidisciplinary approach

“…Twenty patients were carriers of different CREBBP mutations: 17 are described in our previous studies (Bentivegna et al, ; Rusconi et al, ; Spena et al, ) and three are unreported (Table ). One patient showed an EP300 mutation (Negri et al, ), and one was a carrier of a genomic imbalance of chromosome 3 (Gervasini et al, ). Finally, one patient had negative results to the performed tests.…”