Insights into genotype-phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein-Taybi syndrome patients.
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.
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
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Spena
Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore, Policlinico, Milano, Italy.
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Milani
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
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Rusconi
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
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Negri
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
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Colapietro
Department of Pediatrics, Marmara University School of Medicine, Istanbul, Turkey.
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Elcioglu
Clinical Genetics Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
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Bedeschi
Centro di Auxoendocrinologia, Department of Paediatrics, Spedali Civili, Brescia, Italy.
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Pilotta
Department of Obstetrics and Gynecology, Children's Hospital V. Buzzi, Milano, Italy.
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Spaccini
Rare diseases Regional Centre, Pediatric Institute of Maternal-Infantile Sciences Department, Polytechnic University of Marche, Salesi Hospital of United Hospitals of Ancona, Ancona, Italy.
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Ficcadenti
Neonatology and Neonatal Intensive Care Unit, Maternal and Child Department, Parma University, Parma, Italy.
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Magnani
Medical Genetics Department, Gaetano Rummo Hospital, Benevento, Italy.
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Scarano
Department of Pediatrics, Università Milano Bicocca, Fondazione MBBM, San Gerardo Hospital, Monza, Italy.
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Selicorni
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.|Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milano, Italy.
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Larizza
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
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Gervasini
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D055815:Young Adult
D050882:CREB-Binding Protein; C494363:CREBBP protein, human
CREBBP; Rubinstein-Taybi syndrome; bromo/KIX/HAT-domain; genotype-phenotype correlation; point mutation