Autosomal dominant secundum atrial septal defect with various cardiac and noncardiac defects: a new midline disorder

Area of Science:

• Genetics
• Cardiology
• Developmental Biology

Background:

• Atrial septal defects (ASDs) are common congenital heart anomalies.
• Genetic factors play a significant role in the etiology of congenital heart disease.
• Midline developmental disorders can affect multiple organ systems.

Observation:

• A Lebanese family with 12 affected individuals presented with atrial septal defects (ASDs).
• Affected individuals exhibited a spectrum of cardiac anomalies, including conduction defects (left axis deviation, right bundle branch block), arrhythmias (atrial fibrillation, Wolff-Parkinson-White syndrome, nodal atrioventricular rhythm), and valve/outflow tract obstructions (aortic stenosis, pulmonic valve stenosis, Lutembacher syndrome, Ebstein disease).
• Noncardiac abnormalities included hypertelorism, cleft lip, and pectus excavatum, suggesting a broader developmental field defect.

Findings:

• The observed constellation of cardiac and noncardiac anomalies represents a previously undescribed autosomal dominant midline disorder.
• The disorder demonstrates nearly full penetrance and variable expressivity, indicating strong genetic influence with diverse phenotypic manifestations.
• Genetic mapping excluded known loci associated with atrial septal defects or cardiac conduction block, suggesting a novel genetic locus.

Implications:

• This discovery expands our understanding of the genetic basis of congenital heart disease and midline developmental disorders.
• Identification of this novel genetic syndrome provides a new avenue for etiological research and potential therapeutic targets.
• Further investigation into the genetic mutation responsible for this disorder could elucidate fundamental mechanisms of cardiac and craniofacial development.