MYH6 in Congenital Heart Defects: A Genotype-Phenotype Characterization in a French Cohort

Area of Science:

• Cardiovascular Genetics
• Pediatric Cardiology
• Medical Genetics

Background:

• Congenital heart defects (CHD) are common infant anomalies with significant morbidity and mortality.
• Genetic and environmental factors contribute to CHD development.
• MYH6 gene variants are implicated as potential major genetic factors in CHD.

Purpose of the Study:

• To characterize cardiac phenotypes in individuals diagnosed with CHD and carrying MYH6 variants.
• To investigate the association between MYH6 variants and specific CHD subtypes.
• To assess the prevalence of persistent left superior vena cava (LSVC) in this cohort.

Main Methods:

• Retrospective analysis of clinical and family data from 29 individuals with CHD and identified MYH6 variants across four French genetics laboratories.
• Detailed phenotyping and variant analysis.
• Family screening to evaluate penetrance and expressivity.

Main Results:

• Left heart defects were the predominant phenotype (68.9%), including hypoplastic left heart syndrome, left heart obstruction, and coarctation of the aorta.
• Persistent left superior vena cava (LSVC) was observed in 37.9% of cases, a significantly higher prevalence than reported in general literature.
• Most MYH6 variants were heterozygous, missense, and inherited, with evidence of incomplete penetrance and variable expressivity.

Conclusions:

• MYH6 variants are associated with a spectrum of CHD, notably left heart defects and LSVC.
• The findings support the broader molecular screening of the MYH6 gene in patients with CHD.
• Consideration for MYH6 screening is particularly relevant when familial recurrence of CHD is uncertain.