Exome sequencing identifies a novelEP300frame shift mutation in a patient with features that overlap cornelia de lange syndrome

Abstract

Rubinstein-Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS-related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS-related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted.

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

“…The recent discovery of an EP300 mutation in a proband with a Cornelia de Lange syndrome-like phenotype using exome sequencing further suggests the pleiotropic effect of EP300 mutations [Woods et al, 2014]. However, the phenotypic spectrum of EP300 mutations has yet to be fully uncovered, and in order to understand its full spectrum, unbiased genetic screening achieved by exome sequencing would be important.…”

“…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.…”

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…A report of individuals in a family with hairy elbows but with facial features more consistent with FLHS has been published (37). Additionally, there is a recent case of a boy with a CdLS phenotype and a mutation in EP300 (38), a gene mutated in about 3% of individuals with Rubinstein-Taybi syndrome (RSTS, MIM # 180849), which is associated with milder abnormalities of the digits. Finally, the phenotypic overlap between FLHS and RSTS has long been noted (39,40), which is not surprising, given that the gene that causes FLHS, SRCAP, is a coactivator of CREBBP, the gene mutated in the majority of individuals with RSTS.…”

Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

“…Therefore, the molecular mechanism of RSTS appears to be a global transcriptional disturbance due to an altered genome-wide histone modification. Recently, in an individual with features of Cornelia de Lange syndrome (CdLS), an EP300 mutation was identified, suggesting a similar transcriptome disturbance between RSTS and CdLS [Woods et al, 2014].…”