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Clin Genet. 2015 Nov;88(5):431-40. doi: 10.1111/cge.12537. Epub 2014 Dec 9.

Insights into genotype-phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein-Taybi syndrome patients.

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Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore, Policlinico, Milano, Italy.
Department of Pediatrics, Marmara University School of Medicine, Istanbul, Turkey.
Clinical Genetics Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
Centro di Auxoendocrinologia, Department of Paediatrics, Spedali Civili, Brescia, Italy.
Department of Obstetrics and Gynecology, Children's Hospital V. Buzzi, Milano, Italy.
Rare diseases Regional Centre, Pediatric Institute of Maternal-Infantile Sciences Department, Polytechnic University of Marche, Salesi Hospital of United Hospitals of Ancona, Ancona, Italy.
Neonatology and Neonatal Intensive Care Unit, Maternal and Child Department, Parma University, Parma, Italy.
Medical Genetics Department, Gaetano Rummo Hospital, Benevento, Italy.
Department of Pediatrics, Università Milano Bicocca, Fondazione MBBM, San Gerardo Hospital, Monza, Italy.
Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milano, Italy.


The genetic basis of Rubinstein-Taybi syndrome (RSTS), a rare, sporadic, clinically heterogeneous disorder characterized by cognitive impairment and a wide spectrum of multiple congenital anomalies, is primarily due to private mutations in CREBBP (approximately 55% of cases) or EP300 (approximately 8% of cases). Herein, we report the clinical and the genetic data taken from a cohort of 46 RSTS patients, all carriers of CREBBP point mutations. Molecular analysis revealed 45 different gene alterations including 31 inactivating (21 frameshift and 10 nonsense), 10 missense and 4 splicing mutations. Bioinformatic tools and transcript analyses were used to predict the functional effects of missense and splicing alterations. Of the 45 mutations, 42 are unreported and 3 were described previously. Recurrent mutations maybe a key tool in addressing genotype-phenotype correlations in patients sharing the same defects (at the genomic or transcript level) and specific clinical signs, demonstrated here in two cases. The clinical data of our cohort evidenced frequent signs such as arched eyebrows, epicanthus, synophrys and/or frontal hypertrichosis and broad phalanges that, previously overlooked in RSTS diagnosis, now could be considered. Some suggested correlations between organ-specific anomalies and affected CREB-binding protein domains broaden the RSTS clinical spectrum and perhaps will enhance patient follow-up and clinical care.


CREBBP; Rubinstein-Taybi syndrome; bromo/KIX/HAT-domain; genotype-phenotype correlation; point mutation

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