Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect

Am J Med Genet A. 2005 May 15;135(1):47-52. doi: 10.1002/ajmg.a.30684.


Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Family Health
  • Female
  • GATA4 Transcription Factor
  • Heart Septal Defects, Atrial / genetics*
  • Heart Septal Defects, Atrial / pathology
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Phenotype
  • Polymorphism, Single-Stranded Conformational
  • Review Literature as Topic
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • GATA4 Transcription Factor
  • GATA4 protein, human
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • NKX2-5 protein, human
  • Transcription Factors
  • DNA