Genetic analysis of essential cardiac transcription factors in 256 patients with non-syndromic congenital heart defects

Kazuki Kodo, Tsutomu Nishizawa, Michiko Furutani, Shoichi Arai, Kazuaki Ishihara, Mayumi Oda, Shinji Makino, Keiichi Fukuda, Takao Takahashi, Rumiko Matsuoka, Toshio Nakanishi, Hiroyuki Yamagishi

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)


Background: The genetic basis of most congenital heart defects (CHDs), especially non-syndromic and non-familial conditions, remains largely unknown. Methods and Results: DNA samples were collected from immortalized cell lines and original genomes of 256 nonsyndromic, non-familial patients with cardiac outflow tract (OFT) defects. Genes encoding NKX2.5, GATA4, GATA6, MEF2C, and ISL1, essential for heart development, were analyzed using PCR-based bidirectional sequencing. The transcriptional activity of proteins with identified sequence variations was analyzed using a luciferase assay. A novel sequence variant (A103V in MEF2C) was identified, in addition to 4 unreported non-synonymous sequence variants in 3 known causative genes (A6V in NKX2.5, T330R and S339R in GATA4, and E142K in GATA6) in 5 individuals. None of these was found in 500 controls without CHDs. In vitro functional assay showed that all proteins with identified sequence variations exhibited significant changes in transcriptional activity and/or synergistic activity with other transcription factors. Furthermore, overexpression of the A103V MEF2C variant in a fish system disturbed early cardiac development. Conclusions: New mutations in the transcription factors NKX2.5, GATA4, GATA6, and MEF2C that affect their protein function were identified in 2.3% (6/256) of patients with OFT defects. Our results provide the first demonstration of MEF2C mutation and suggest that disturbances in the regulatory circuits involving these cardiac transcription factors may cause a subset of non-syndromic and non-familial CHDs.

Original languageEnglish
Pages (from-to)1703-1711
Number of pages9
JournalCirculation Journal
Issue number7
Publication statusPublished - 2012


  • Congenital heart defects
  • Genetics
  • Genotype
  • Pediatrics
  • Screening

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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