Rubinstein-Taybi 2 associated to novel EP300 mutations: deepening the clinical and genetic spectrum

Abstract

BackgroundRubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50–60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations.MethodsPatients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study. MLPA and panel-based NGS EP300 were performed.ResultsEight patients were found to carry EP300 mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures, columella below the alae nasi, and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties).ConclusionsThe clinical evaluation of our patients corroborates that clinical features in EP300 are less marked than in CREBBP patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring EP300 mutations could present a different phenotype. Broadening the knowledge about EP300-RSTS phenotype may contribute to improve the management of patients and the counselling to the families.

EP300‐related Rubinstein–Taybi syndrome: Highlighted rare phenotypic findings and a genotype–phenotype meta‐analysis of 74 patients

“…We organized the genotype data for our 12 unpublished patients along with 90 previously published distinct cases from the literature, (Bartholdi et al, 2007;Bartsch et al, 2010;Bounakis, Karampalis, Sharp, & Tsirikos, 2015;Fergelot et al, 2016;Foley, Bunyan, Stratton, Dillon, & Lynch, 2009;Hadzsiev, Gyorsok, Till, Czako, & Bartsch, 2019;Hamilton et al, 2016;Lopez et al, 2018;Masuda et al, 2015;Menke et al, 2018;Negri et al, 2015;Negri et al, 2016;Roelfsema et al, 2005;Sellars, Sullivan, & Schaefer, 2016;Solomon et al, 2015;Tamhankar, Merchant, & Shah, 2016;Tsai et al, 2011;Wincent et al, 2016;Woods et al, 2014;Zimmermann et al, 2007) based on mutation type (missense or in-frame vs. all other mutations) and position in the gene. To determine gene domains we used https://www.ncbi.nlm.nih.gov/gene/2033 updated March 22, 2020 and accessed on March 29, 2020.…”

“…Genotype-phenotype correlations have been proposed, especially concerning EP300, with loss or interruption of the catalytic lysine acetyltransferase domain (HAT/KAT11) proposed to be particularly deleterious, and patients who harbor mutations not affecting the HAT domain of the gene proposed to have a milder phenotype and less severe intellectual disability (Hamilton et al, 2016;Lopez et al, 2018). Other publications reference that mutations closer to the 3 0 -end of the protein may have a less deleterious effect (Bartsch et al, 2010;Hamilton et al, 2016;Lopez et al, 2018;Zimmermann, Acosta, Kohlhase, & Bartsch, 2007). It has also been suggested that it is not only the mutation domain but the mutation type that predicts disease severity, with certain missense variants, especially those in the last exons of the gene-exons 30 and 31proposed to have a novel gain-of-function effect (Menke et al, 2018), as opposed to the haploinsufficiency mechanism generally cited as causal.…”

Rubinstein–Taybi syndrome in diverse populations

“…Numbers on the pictures correspond to patients ID in Table S1. Sex, age, and country of origin available in Table S1 [Color figure can be viewed at wileyonlinelibrary.com] Taine, & Battin, 1992;Li & Szybowska, 2010;López et al, 2018;Münevveroglu & Akgöl, 2011;Negri et al, 2016;Okoroma & Izuora, 1987;Shah, Singh, Vijayan, & Girisha, 2011;Solomon et al, 2015;Tamhankar, Merchant, & Shah, 2016;Tang, Guo, Linpeng, & Wu, 2019;Tsai et al, 2011;Van Genderen, Kinds, Riemslag, & Hennekam, 2000;Verhoeven et al, 2009;Wieczorek et al, 2009;Wójcik et al, 2010;Woods et al, 2014;Yamamoto et al, 2005). Images of patients with permission to publish are shown in Figures 1-4 Figure S1).…”

New point mutation in CREBBP Gene cause Rubinstein-Taybi syndrome: A case report

“…Approximately 60% of RSTS is caused by CREBBP(16p13, OMIM#600140) gene mutation, which is RSTS-1; 10% is caused by EP300 gene mutation, which is RSTS-2 [7] , 30% of which have not yet found a disease-causing gene. The clinical manifestations are mainly facial dysmorphic features like prominent forehead, low anterior hairline and grimacing smile, microcephaly, short stature, high arched eyebrows, long eyelashes, oblique eyelids, wide nose bones, high palate and minor jaw deformity.…”