CLINICAL REPORT Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP Andrea Angius 1† | Paolo Uva 2† | Manuela Oppo 1,3 | Ivana Persico 1 | Stefano Onano 1,3 | Stefania Olla 1 | Valentina Pes 4 | Chiara Perria 4 | Gianmauro Cuccuru 2 | Rossano Atzeni 2 | Gigliola Serra 4 | Francesco Cucca 1,3 | Stefano Sotgiu 4 | Raoul C. Hennekam 5† | Laura Crisponi 1,3† 1 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato (CA), Italy 2 Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, Pula (CA), Italy 3 Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy 4 Clinica di Neuropsichiatria Infantile, Dipartimento di Scienze Mediche, Chirurgiche e Sperimentali, Università degli Studi di Sassari, Sassari, Italy 5 Department of Pediatrics, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, the Netherlands Correspondence Laura Crisponi, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Cagliari, Monserrato (CA) 09042 Italy. Email: laura.crisponi@irgb.cnr.it Funding information Sardinian Autonomous Region, Grant/Award Numbers: (Legge Regionale 7 agosto 2007, n.7: "Promozione d, CRP-59829 We report here a novel de novo missense variant affecting the last amino acid of exon 30 of CREBBP [NM_004380, c.5170G>A; p.(Glu1724Lys)] in a 17-year-old boy presenting mild intellec- tual disability and dysmorphisms but not resembling the phenotype of classical Rubinstein–Taybi syndrome. The patient showed a marked overweight from early infancy on and had cortical het- erotopias. Recently, 22 individuals have been reported with missense mutations in the last part of exon 30 and the beginning of exon 31 of CREBBP, showing this new phenotype. This additional case further delineates the genotype–phenotype correlations within the molecular and pheno- typic spectrum of variants in CREBBP and EP300. KEYWORDS CREB-binding protein, exon 30, new phenotype, Rubinstein–Taybi syndrome, whole exome sequencing 1 | INTRODUCTION Rubinstein–Taybi syndrome (RSTS, MIM#180849, MIM#613684) is a rare congenital, plurimalformative, and neurodevelopmental disorder with an autosomal-dominant inheritance first described in 1963 (Hennekam, Stevens, & Van de Kamp, 1990; Rubinstein, 1963; Ste- vens, 2002). The estimated incidence is 1 in 100,000–125,000 live births (Hennekam et al., 1990). It is primarily characterized by facial abnormalities, moderate or severe intellectual disability, skeletal anomalies and short stature. Main additional features include distinc- tively broad and/or angled thumbs and great toes may be present. Clinical diagnosis can be complicated by the heterogeneous clinical presentation and the lack of an internationally accepted definition of the phenotype. The etiology is linked to two functionally related genes: CREBBP and EP300. Both encode for nuclear proteins, ubiquitously expressed, acting as transcriptional coactivators in multiple processes such as DNA repair, growth and differentiation (Goodman & Smolik, 2000). CBP possesses several domains including ZNF1 = zinc finger, TAZ- type (344–439); KIX = CREB-binding domain (587–672); Br = bromo- domain (1066–1,201); KAT = histone acetyltransferase domain (1323–1,700 de novo); ZNF2 = zinc finger, ZZ-type (1701–1,744); ZNF3 = zinc finger, TAZ-type (1764–1853); and NR = nuclear recep- tor coactivator (2019–2,115; Menke et al., 2018). Variants in CREBBP † Andrea Angius, Paolo Uva, Raoul C. Hennekam, and Laura Crisponi authors contributed equally to this work. Received: 23 November 2018 Revised: 28 December 2018 Accepted: 1 January 2019 DOI: 10.1002/ajmg.a.61052 Am J Med Genet. 2019;1–5. wileyonlinelibrary.com/journal/ajmga © 2019 Wiley Periodicals, Inc. 1