Pediatric Cardiology

, Volume 39, Issue 4, pp 794–804 | Cite as

A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle

  • Cai-Xia Lu
  • Wei Wang
  • Qian Wang
  • Xing-Yuan Liu
  • Yi-Qing Yang
Original Article


Congenital heart defect (CHD) represents the most prevalent birth defect, and accounts for substantial morbidity and mortality in humans. Aggregating evidence demonstrates the genetic basis for CHD. However, CHD is a heterogeneous disease, and the genetic determinants underlying CHD in most patients remain unknown. In the present study, a cohort of 186 unrelated cases with CHD and 300 unrelated control individuals were recruited. The coding exons and flanking introns of the MEF2C gene, which encodes a transcription factor crucial for proper cardiovascular development, were sequenced in all study participants. The functional effect of an identified MEF2C mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect. Analysis of the proband’s pedigree showed that the mutation co-segregated with CHD with complete penetrance. The missense mutation, which changed the evolutionarily conserved amino acid, was absent in 300 control individuals. Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity. Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD. This study firstly associates MEF2C loss-of-function mutation with DORV in humans, which provides novel insight into the molecular pathogenesis of CHD, suggesting potential implications for genetic counseling and personalized treatment of CHD patients.


Congenital heart disease Double outlet right ventricle Genetics Transcription factor MEF2C Reporter gene assay 



We sincerely thank the study subjects for their dedication to the research. This work was financially supported by grants from the National Natural Science Foundation of China (81470372) and the Natural Science Foundation of Shanghai, China (16ZR1432500).

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interests.

Supplementary material

246_2018_1822_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 12 KB)


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Authors and Affiliations

  1. 1.Department of Pediatrics, Huashan Hospital NorthFudan UniversityShanghaiChina
  2. 2.Department of Parasitology, School of Basic Medical ScienceAnhui Medical UniversityHefeiChina
  3. 3.Department of Pediatrics, Tongji HospitalTongji University School of MedicineShanghaiChina
  4. 4.Department of CardiologyShanghai Chest Hospital, Shanghai Jiao Tong UniversityShanghaiChina
  5. 5.Department of Cardiovascular Research LaboratoryShanghai Chest Hospital, Shanghai Jiao Tong UniversityShanghaiChina
  6. 6.Department of Central LaboratoryShanghai Chest Hospital, Shanghai Jiao Tong UniversityShanghaiChina

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