Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot
| Autor: | Phil Barnett, Bruno Dallapiccola, Cornelis J. Boogerd, Monica Marini, Pietro Sirleto, Sonia B. Albanese, Margherita Lerone, Alex V. Postma, Monica Pelegrini, Roberto Ravazzolo, Antonella Santilli, Gianluca Trocchio, Anwar Baban, Giacomo Pongiglione, Maria Cristina Digilio |
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| Přispěvatelé: | Amsterdam Cardiovascular Sciences, Medical Biology, Other departments |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Mutation Missense Biology medicine.disease_cause Polymerase Chain Reaction Bilateral triphalangeal thumbs Atrial septal defects Exon Internal medicine Genetics medicine Humans Immunoprecipitation cardiovascular diseases Luciferases Genetics (clinical) DNA Primers Tetralogy of Fallot Homeodomain Proteins Mutation GATA4 Sequence Analysis DNA medicine.disease Phenotype GATA4 Transcription Factor Pedigree Italy Homeobox Protein Nkx-2.5 cardiovascular system Cardiology Female T-Box Domain Proteins Atrioventricular block Transcription Factors |
| Zdroj: | Europe PubMed Central American journal of medical genetics. Part A, 164A(12), 3100-3107. Wiley-Liss Inc. |
| ISSN: | 1552-4825 |
| Popis: | Tetralogy of Fallot (TOF) (OMIM #187500) is the most frequent conotruncal congenital heart defect (CHD) with a range of intra- and extracardiac phenotypes. TBX5 is a transcription factor with well-defined roles in heart and forelimb development, and mutations in TBX5 are associated with Holt-Oram syndrome (HOS) (OMIM#142900). Here we report on the screening of 94 TOF patients for mutations in TBX5, NKX2.5 and GATA4 genes. We identified two heterozygous mutations in TBX5. One mutation was detected in a Moroccan patient with TOF, a large ostium secundum atrial septal defect and complete atrioventricular block, and features of HOS including bilateral triphalangeal thumbs and fifth finger clinodactyly. This patient carried a previously described de novo, stop codon mutation (p.R279X) located in exon 8 causing a premature truncated protein. In a second patient from Italy with TOF, ostium secundum atrial septal defect and progressive arrhythmic changes on ECG, we identified a maternally inherited novel mutation in exon 9, which caused a substitution of a serine with a leucine at amino acid position 372 (p.S372L, c.1115C>T). The mother's clinical evaluation demonstrated frequent ventricular extrasystoles and an atrial septal aneurysm. Physical examination and radiographs of the hands showed no apparent skeletal defects in either child or mother. Molecular evaluation of the p.S372L mutation demonstrated a gain-of-function phenotype. We also review the literature on the co-occurrence of TOF and HOS, highlighting its relevance. This is the first systematic screening for TBX5 mutations in TOF patients which detected mutations in two of 94 (2.1%) patients. © 2014 Wiley Periodicals, Inc |
| Databáze: | OpenAIRE |
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