Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap cornelia de lange syndrome. Issue 1 (29th October 2013)

• Record Type: Journal Article
• Authors: Woods, Susan A.; Robinson, Haynes B.; Kohler, Lisa J.; Agamanolis, Dimitris; Sterbenz, George; Khalifa, Mohamed
• Is Part Of: American journal of medical genetics. Volume 164:Issue 1(2014.)
• Page Start: 251
• Page End: 258
• Publication Date: 2013-10-29
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.36237
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajmga36237-sec-0001" sec-type="section"> <p>Rubinstein–Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (<italic>CREBBP</italic> and <italic>EP300</italic>) are known to cause RTS, and five (<italic>NIPBL</italic>, <italic>SMC1A</italic>, <italic>SMC3</italic>, <italic>RAD21</italic>, and <italic>HDAC8</italic>) 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 <italic>EP300</italic> and <italic>CREBBP</italic> encode homologous proteins and perform similar functions, only eight <italic>EP300</italic> positive RTS patients have been reported, suggesting that patients with <italic>EP300</italic> 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 <italic>EP300</italic> mutation was found on whole exome sequencing. Possible links between <italic>EP300</italic> and genes causing CdLS are evident in the literature. Both <italic>EP300</italic> and <italic>HDAC8</italic> are involved in the regulation of <italic>TP53</italic> 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 <italic>EP300</italic> 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 <italic>EP300</italic> mutations should be better understood. In the meantime, testing for <italic>EP300</italic> mutations in those with features of CdLS may be warranted. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>