Individuals with no need for arrhythmia genetic testing can be identified as carriers of pathogenic or likely pathogenic (P/LP) mutations by sequencing Mendelian arrhythmia genes. However, it was unclear whether these mutations were related to clinically significant symptoms before or after the return of variant data. Furthermore, the bulk of newly identified variations was classed as variants of unknown significance, restricting clinical actionability.
The eMERGE-III (Electronic Medical Records and Genomics Phase III) trial comprised 21,846 individuals who had no previous need for cardiac genetic testing. Participants had their Mendelian disease genes sequenced, including 10 associated with arrhythmia disorders. Variant carriers were evaluated using phenotypes collected from electronic health records and a follow-up clinical assessment. Automated electrophysiological studies in HEK293 cells were used to describe selected variations of questionable significance (n=50).
P/LP variations were found in 3.0% of the 109 genes, as previously reported. Researchers presented 120 patients (0.6%) having P/LP arrhythmia variations. Arrhythmia P/LP carriers showed a considerably greater burden of arrhythmia phenotypes in their electronic health records than noncarriers. Variant findings were returned to 54 individuals. About 19 of the 54 subjects were diagnosed with an inherited arrhythmia condition (mostly long-QT syndrome), and 12 of these 19 diagnoses were obtained only after variant data were returned (0.05%). They categorized 11 variations as likely benign and 8 as P/LP after in vitro functional assessment of 50 variants of unknown importance.
In a broad population with no need for arrhythmia genetic testing, genome sequencing revealed phenotype-positive bearers of mutations in congenital arrhythmia syndrome illness genes. As more people’s genomes were sequenced, the illness risk from uncommon mutations in arrhythmia genes might be determined by combining genomic screening, phenotypes from electronic health records, and in vitro functional research.