Clinical and molecular characterization of Rubinstein‐Taybi syndrome patients carrying distinct novel mutations of the EP300 gene

Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by postnatal growth deficiency, skeletal abnormalities, dysmorphic features and cognitive deficit. Mutations in two genes, CREBBP and EP300, encoding two homologous transcriptional co-activators, have been identified in ˜55% and ˜3-5% of affected individuals, respectively. To date, only eight EP300-mutated RSTS patients have been described and 12 additional mutations are reported in the database LOVD. In this study, EP300 analysis was performed on 33 CREBBP-negative RSTS patients leading to the identification of six unreported germline EP300 alterations comprising one deletion and five point mutations. All six patients showed a convincing, albeit mild, RSTS phenotype with minor skeletal anomalies, slight cognitive impairment and few major malformations. Beyond the expansion of the RSTS-EP300-mutated cohort, this study indicates that EP300-related RSTS cases occur more frequently than previously thought (˜8% vs 3-5%); furthermore, the characterization of novel EP300 mutations in RSTS patients will enhance the clinical practice and genotype-phenotype correlations.

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein–Taybi and Filippi syndromes

“…1 RTS is caused by variants in CREBBP (~50-60% of the cases) 3,10-12 and EP300 (~3-8%). 4,13 Although the features of the proband are consistent with RTS (Table 1), characteristic facial features, most notably the beaked nose and grimacing smile, are absent. Though the patient has a relatively small head size, there is no microcephaly.…”

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

“…RSTS is caused by heterozygous mutations in the CBP and EP300 genes [Roelfsema et al, 2005]. In about 55% of the RSTS cases, mutations are found in CBP , whereas mutations in EP300 have been identified only in up to 8% of the cases [Roelfsema et al, 2005;Hennekam, 2006;Negri et al, 2015]. Mutations in CBP cause the most typical RSTS phenotype, and although EP300 mutations can be found in typical RSTS cases, a wider phenotypic spectrum is seen in individuals with EP300 mutations [Roelfsema et al, 2005;Bartholdi et al, 2007;Negri et al, 2015].…”

“…Mutations in CBP cause the most typical RSTS phenotype, and although EP300 mutations can be found in typical RSTS cases, a wider phenotypic spectrum is seen in individuals with EP300 mutations [Roelfsema et al, 2005;Bartholdi et al, 2007;Negri et al, 2015]. Given the genomic deletions of CBP or EP300 causing the typical phenotype of RSTS, haploinsufficiency of either CBP or EP300 is suggested as the disease mechanism of RSTS [Roelfsema et al, 2005;Bartholdi et al, 2007;Tsai et al, 2011;Negri et al, 2015Negri et al, , 2016Rusconi et al, 2015]. These genes encode transcriptional coactivators with lysine acetyltransferase activity ( fig.…”

A case with Rubinstein-Taybi syndrome: A novel frameshift mutation in the CREBBP gene

“…Mutations in EP300 have been identified in up to 8% of the cases with RSTS. 5,6 In about 40% of clinically diagnosed cases with RTS, the genetic cause remains unknown.…”