Complementary Yield of Gene Panel Testing and ACMG SF v3.3 Screening for Cardiovascular Disease in a Korean Cohort

ABSTRACT

Inherited arrhythmia syndromes and cardiomyopathies are genetically heterogeneous, and clinical exome sequencing (CES) for unrelated indications increasingly yields cardiovascular secondary findings (SFs) under the ACMG SF v3.3 list. We compared, at a single Korean centre, phenotype‐directed cardiac gene panel testing with opportunistically ascertained cardiovascular SFs. Forty patients with suspected inherited arrhythmia or cardiomyopathy underwent a 19‐gene arrhythmia or 173‐gene cardiomyopathy panel with AI‐assisted, manually reviewed variant classification; separately, 288 patients undergoing CES for unrelated indications were screened for ACMG SF v3.3 cardiovascular pathogenic/likely pathogenic variants. A phenotype‐concordant pathogenic/likely pathogenic variant was found in 8/40 patients (20.0%), including a recurrent KCNQ1 p.Arg231His variant in two unrelated infants and a MYBPC3 variant upgraded to pathogenic by co‐segregation in a mother‐son pair. Among the 288 exome‐sequenced patients, 17 reportable cardiovascular SFs occurred in 16 (5.6%), predominantly dilated cardiomyopathy ( n  = 7, mostly TTN ) and familial hypercholesterolaemia ( n  = 6, including a recurrent PCSK9 p.Glu32Lys variant in three patients). The two approaches sampled largely non‐overlapping gene categories and are complementary rather than competing; recurrent, population‐specific variants underscore the need for population‐informed interpretation and structured counselling in cardiovascular genetic diagnosis.