Confirmation of EP300 gene mutations as a rare cause of Rubinstein–Taybi syndrome

Zimmermann, Nicole; Acosta, Ana M. Bravo Ferrer; Kohlhase, Jürgen; Bartsch, Oliver

doi:10.1038/sj.ejhg.5201791

Cited by 80 publications

(77 citation statements)

References 18 publications

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“…Our case is only the seventh case reported to date. 3,4,11,12 The true percentage of RSTS caused by EP300 alterations and the full phenotypic picture of EP300 RSTS is therefore unclear. The diagnosis in our case was considered because of the typical RSTS facial dysmorphism.…”

Section: Discussionmentioning

confidence: 99%

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Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein–Taybi syndrome detected by aCGH

et al. 2010

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We demonstrate the utility of an exon coverage microarray platform in detecting intragenic deletions: one in exons 24-27 of the EP300 gene and another in exons 27 and 28 of the CREBBP gene in two patients with Rubinstein-Taybi syndrome (RSTS). RSTS is a heterogeneous disorder in which B45-55% of cases result from deletion or mutations in the CREBBP gene and an unknown portion of cases result from gene changes in EP300. The first case is a 3-year-old female with an exonic deletion of the EP300 gene who has classic facial features of RSTS without the thumb and great toe anomalies, consistent with the milder skeletal phenotype that has been described in other RSTS cases with EP300 mutations. In addition, the mother of this patient also had preeclampsia during pregnancy, which has been infrequently reported. The second case is a newborn male who has the classical features of RSTS. Our results illustrate that exon-targeted array comparative genomic hybridization (aCGH) is a powerful tool for detecting clinically significant intragenic rearrangements that would be otherwise missed by aCGH platforms lacking sufficient exonic coverage or sequencing of the gene of interest.

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Section: Discussionmentioning

confidence: 99%

“…Although six other cases of EP300 RSTS have been previously reported, 3,4,11,12 this is the first patient ascertained by microarray analysis in a clinical setting.…”

Section: Introductionmentioning

confidence: 85%

Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein–Taybi syndrome detected by aCGH

et al. 2010

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“…In general, the phenotypic features associated with EP300 mutations are reported to be less severe and quite variable compared to typical RSTS cases with underlying CREBBP mutations [Roelfsema et al, 2005;Bartholdi et al, 2007;Zimmermann et al, 2007;Foley et al, 2009;Bartsch et al, 2010;Tsai et al, 2011;Woods et al, 2014]. However, such phenotypic variation has been identified in cohorts of individuals that are suspected of having RSTS features; therefore, it is possible that EP300 mutations cause phenotypic features that are not considered typical for RSTS.…”

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confidence: 99%

Exome Sequencing Identification of <b><i>EP300</i></b> Mutation in a Proband with Coloboma and Imperforate Anus: Possible Expansion of the Phenotypic Spectrum of Rubinstein-Taybi Syndrome

et al. 2015

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Rubinstein-Taybi syndrome (RSTS) is a multisystem developmental disorder characterized by facial dysmorphisms, broad thumbs and halluces, growth retardation, and intellectual disability. In about 8% of RSTS cases, mutations are found in EP300. Previously, the EP300 mutation has been shown to cause the highly variable RSTS phenotype. Using exome sequencing, we identified a de novo EP300 frameshift mutation in a proband with coloboma, facial asymmetry and imperforate anus with minimal RSTS features. Previous molecular studies have demonstrated the importance of EP300 in oculogenesis, supporting the possibility that EP300 mutation may cause ocular coloboma. Since a wide phenotypic spectrum is well known in EP300-associated RSTS cases, the atypical phenotype identified in our proband may be an example of rare manifestations of RSTS.

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“…10 EP300 mutations are comparatively rare as only six have been described so far, in six patients with a mild clinical presentation. 6,[18][19][20] The pathological mechanism has been clarified in approximately 60% of the cases, but multiple cryptic mutational mechanisms of the major CBP gene may be overlooked, including mosaic point mutations, mutations affecting the 5¢ and 3¢ UTRs, promoter epimutations and alterations at post-transcriptional or translational levels.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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.

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Confirmation of EP300 gene mutations as a rare cause of Rubinstein–Taybi syndrome

Cited by 80 publications

References 18 publications

Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein–Taybi syndrome detected by aCGH

Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein–Taybi syndrome detected by aCGH

Exome Sequencing Identification of <b><i>EP300</i></b> Mutation in a Proband with Coloboma and Imperforate Anus: Possible Expansion of the Phenotypic Spectrum of Rubinstein-Taybi Syndrome

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

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