Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot

Anwar Baban, Alex Vincent Postma, Monica Marini, Gianluca Trocchio, Antonella Santilli, Monica Pelegrini, Pietro Sirleto, Margherita Lerone, Sonia Bernadette Albanese, Phil Barnett, Cornelis Job Boogerd, Bruno Dallapiccola, Maria Cristina Digilio, Roberto Ravazzolo, Giacomo Pongiglione

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3100-3107
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume164
Issue number12
DOIs
Publication statusPublished - Dec 1 2014

Keywords

  • Atrial septal defects
  • Conduction defects
  • Gain-of-function mutation
  • TBX5 mutations
  • Tetralogy of Fallot (TOF)

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

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  • Cite this

    Baban, A., Postma, A. V., Marini, M., Trocchio, G., Santilli, A., Pelegrini, M., Sirleto, P., Lerone, M., Albanese, S. B., Barnett, P., Boogerd, C. J., Dallapiccola, B., Digilio, M. C., Ravazzolo, R., & Pongiglione, G. (2014). Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot. American Journal of Medical Genetics, Part A, 164(12), 3100-3107. https://doi.org/10.1002/ajmg.a.36783