Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification...

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Familial bradycardia is increasingly studied using next-generation sequencing (NGS).
• Many identified genetic variants lack comprehensive evaluation, necessitating a reevaluation of genetic factors in bradycardia.
• Understanding the genetic basis of bradycardia is crucial for accurate diagnosis and treatment.

Purpose of the Study:

• To summarize genetic studies on familial bradycardia.
• To reevaluate the relationship between genetic factors and bradycardia.
• To identify high-priority genes associated with familial bradycardia.

Main Methods:

• Systematic literature search of PubMed from 2008 to 2019.
• Analysis of sequence variants using the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) classification framework.
• Identification and classification of genes implicated in familial bradycardia.

Main Results:

• 88 articles, 99 sequence variants, and 34 genes were identified.
• 13 genes (ABCC9, ACTN2, CACNA1C, DES, HCN4, KCNQ1, KCNH2, LMNA, MECP2, LAMP2, NPPA, SCN5A, TRPM4) were classified as high-priority for familial bradycardia.
• Many implicated genes are associated with diverse clinical manifestations.

Conclusions:

• 13 high-priority genes are recommended for genetic evaluation in patients with familial bradycardia.
• Genetic variants should be rigorously evaluated using the ACMG/AMP framework prior to publication.
• Standardized variant evaluation is essential for advancing the genetic understanding of bradycardia.