The prevalence of laterality defects in patients with congenital heart disease

Area of Science:

• Medical Genetics
• Developmental Biology
• Cardiology

Background:

• Congenital heart disease (CHD) affects about 1% of newborns.
• Laterality defects, such as situs inversus and heterotaxy, occur more frequently in CHD patients.
• Comprehensive studies on the genetic basis of CHD with laterality defects are limited.

Purpose of the Study:

• To determine the prevalence of laterality defects in a large cohort of CHD patients.
• To investigate the association between specific complex CHD phenotypes and laterality defects.
• To identify genetic variants associated with CHD and laterality defects using whole-exome sequencing.

Main Methods:

• Retrospective analysis of 18,781 CHD patients to identify laterality defects.
• Binary logistic regression to evaluate associations between CHD phenotypes and laterality defects.
• Whole-exome sequencing (WES) on 121 CHD patients with laterality defects.

Main Results:

• 1.1% of CHD patients exhibited laterality defects (situs inversus totalis: 0.4%, situs ambiguus: 0.7%).
• Laterality defects were more prevalent in complex CHD (5.4%) than simple CHD (0.4%).
• Single atrium with single ventricle (SA+SV) showed a strong association with laterality defects (OR=48.23).
• WES identified pathogenic variants in 13.2% of patients, including known genes (e.g., ZIC3, NKX2-5) and novel candidate genes.

Conclusions:

• Laterality defects are significantly associated with CHD, particularly complex forms like SA+SV.
• Genetic analysis reveals both established and novel gene candidates contributing to CHD with laterality defects.
• This study enhances understanding of the genetic etiology of CHD and laterality abnormalities.