Genetics of congenital arrhythmia syndromes: the challenge of variant interpretation

Congenital arrhythmia syndromes are rare genetic disorders that can cause a high risk of sudden cardiac death. Expert panels have affirmed 15 genes that are linked to congenital arrhythmias. These genes mostly encode cardiac ion channel proteins or associated regulatory proteins that generate the cardiac action potential. Common genetic variation modulates the risk of rare variants and partially explains the incomplete penetrance of these disorders. As genetic testing becomes more prevalent, a major challenge is that most detected variants are annotated as variants of uncertain significance. This review will highlight emerging methods that are refining our understanding of arrhythmia genetics, including phenotype risk scores, large cohorts, in vitro functional assays, structural models, and computational predictions.