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

Area of Science:

• Genetics
• Cardiovascular Biology
• Developmental Biology

Background:

• Congenital heart defect (CHD) is the most common birth defect, with significant morbidity and mortality.
• While the genetic basis of CHD is recognized, specific genetic determinants remain largely unknown for many patients.
• MEF2C is a transcription factor critical for cardiovascular development.

Purpose of the Study:

• To investigate the genetic basis of CHD by sequencing the MEF2C gene in patients and controls.
• To characterize the functional impact of identified MEF2C mutations on cardiovascular development.
• To establish a potential link between MEF2C mutations and specific types of CHD, such as DORV.

Main Methods:

• Sequencing of the MEF2C gene (coding exons and flanking introns) in 186 unrelated CHD cases and 300 unrelated controls.
• Functional analysis of a novel MEF2C mutation (p.R15C) using a dual-luciferase reporter assay.
• Pedigree analysis to assess co-segregation of the mutation with CHD.

Main Results:

• A novel heterozygous MEF2C mutation, p.R15C, was identified in a patient with double outlet right ventricle (DORV) and ventricular septal defect.
• The identified mutation was absent in 300 control individuals and co-segregated with CHD in the patient's family with complete penetrance.
• Functional assays demonstrated that the mutant MEF2C protein exhibits significantly reduced transcriptional activity and impaired synergistic activation with GATA4.

Conclusions:

• This study provides the first evidence linking a loss-of-function MEF2C mutation to DORV in humans.
• The findings deepen the understanding of the molecular pathogenesis of CHD.
• This discovery has potential implications for genetic counseling and personalized treatment strategies for CHD patients.