Skipping of Exon 20 in EP300: A Novel Variant Linked to Rubinstein-Taybi Syndrome With Atypical and Severe Clinical Manifestations. in Clinical genetics / Clin Genet. 2025 Mar;107(3):354-358. doi: 10.1111/cge.14654. Epub 2024 Nov 27.

2025
AO Cuneo
AOU San Luigi di Orbassano
AOU Città della Salute di Torino

Tipo pubblicazione

Journal Article

Autori/Collaboratori (19)Vedi tutti...

Ferrero GB
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Brusco A
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Buxbaum JD
Endocrinology Unit, Fondazione IRCCS ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

et alii...

Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of CREBBP (RSTS1) and EP300 (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype-phenotype correlation, except for specific variants which cause the allelic Menke-Hennekam syndrome. Trio exome analysis, data collection via networking and GeneMatcher platforms, transcript processing analysis, and DNA methylation profiling were performed. We identified two unrelated patients with de novo variants in EP300 (NM_001429.4: c.3671+5G>C; c.3671+5_3671+8delGTAA) predicted to cause in-frame exon 20 skipping, confirmed in one patient. In silico 3D protein modeling suggested that exon 20 deletion (comprising 27 amino acids) likely alters the structural conformation between the RING_CBP-p300 and HAT-KAT11 domains. Clinically, both patients displayed severe RSTS2-like clinical features, including autism spectrum disorder, speech delay, hearing loss, microcephaly, developmental delay, and intellectual disability, alongside ocular, respiratory, and cardiovascular abnormalities. Additionally, one patient developed early-onset colorectal cancer. DNA methylation profiling in Subject #1 confirmed RSTS but did not align with the specific episignatures for RSTS1 or RSTS2. We propose that skipping of exon 20 in EP300 is associated with a distinct form of Rubinstein-Taybi syndrome featuring clinical characteristics not fully aligning with RSTS1 or RSTS2. Our findings increase the understanding of RSTS genetic and molecular basis and stress the need for further research to establish definitive genotype-phenotype correlations.

Accesso banca dati bibliografica

PMID : 39603792

DOI : 10.1111/cge.14654

Keywords

Rubinstein–Taybi; EP300; GNAS; Haploinsufficiency/genetics; CREB-Binding Protein/genetics; Genetic Predisposition to Disease; DNA Methylation/genetics; Mutation; Child, Preschool; Exome Sequencing; Phenotype; Child; Genetic Association Studies; Female; Exons/genetics; Male; E1A-Associated p300 Protein/genetics; episignature; Rubinstein-Taybi Syndrome/genetics/pathology; Humans; p300 ring domain;