Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Area of Science:

• Cardiology
• Genetics
• Pediatrics

Background:

• Sudden death in children is rare but impactful, often presenting as the first symptom in healthy individuals.
• Autopsies are inconclusive in 40-50% of pediatric cases, leading to a suspected diagnosis of sudden arrhythmic death syndrome.
• Molecular autopsy identifies genetic causes in nearly 30% of sudden deaths in children under 16.

Purpose of the Study:

• To review the current state of genetic diagnosis for inherited arrhythmogenic diseases in pediatric sudden death.
• To highlight challenges in genotype-phenotype association and variant classification.
• To facilitate the clinical translation of genetic findings for risk stratification and family counseling.

Main Methods:

• Review of recent publications on gene curation and genotype-phenotype associations.
• Analysis of cases with genetic overlap in arrhythmogenic diseases.
• Examination of advancements in classifying variants of uncertain significance.

Main Results:

• Progress is being made in gene curation and understanding genotype-phenotype relationships.
• Genetic overlap between different arrhythmogenic conditions complicates diagnosis.
• New approaches are emerging for classifying variants of uncertain significance.

Conclusions:

• Despite advances, many families lack a definitive genetic cause for unexpected pediatric death.
• Accurate genotype-phenotype correlation and variant classification are crucial for clinical application.
• Improved genetic diagnostic strategies are needed to aid risk assessment, treatment, and genetic counseling for families affected by pediatric sudden death.