title: Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot.
abstract: 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.
authors.affiliation: Department of Pediatric Cardiology and Cardiosurgery, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
authors.forename: Anwar
authors.initials: A
authors.lastname: Baban
authors.forename: Alex Vincent
authors.initials: AV
authors.lastname: Postma
authors.forename: Monica
authors.initials: M
authors.lastname: Marini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Trocchio
authors.forename: Antonella
authors.initials: A
authors.lastname: Santilli
authors.forename: Monica
authors.initials: M
authors.lastname: Pelegrini
authors.forename: Pietro
authors.initials: P
authors.lastname: Sirleto
authors.forename: Margherita
authors.initials: M
authors.lastname: Lerone
authors.forename: Sonia Bernadette
authors.initials: SB
authors.lastname: Albanese
authors.forename: Phil
authors.initials: P
authors.lastname: Barnett
authors.forename: Cornelis Job
authors.initials: CJ
authors.lastname: Boogerd
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Giacomo
authors.initials: G
authors.lastname: Pongiglione
mesh_terms: D017931:DNA Primers / Q000235:genetics; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D007558:Italy; D008156:Luciferases; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D020825:T-Box Domain Proteins / Q000235:genetics*; D013771:Tetralogy of Fallot / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D017931:DNA Primers; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D008156:Luciferases
keywords: TBX5 mutations; Tetralogy of Fallot (TOF); atrial septal defects; conduction defects; gain-of-function mutation