Family screening for genetic cardiomyopathies in ECG-positive phenotype-negative adolescents: a joint clinical and genetic approach

Abstract Adolescents may present with abnormal ECG findings despite having no structural or electrical evidence of cardiomyopathy. The value of extending family screening to this subgroup remains uncertain. To evaluate the impact of family screening in ECG-positive phenotype-negative adolescents, and determine whether a joint clinical-genetic approach improves the diagnostic yield. In this prospective cohort study, adolescents with an abnormal ECG identified through a nationwide screening program underwent comprehensive clinical/genetic evaluation. Phenotype-negative individuals were included. Relatives underwent clinical screening, with cascade genetic testing offered when probands carried a likely/definite pathogenic (LP/P) cardiomyopathy variant. Abnormal screening outcomes included relatives with (i) de novo cardiomyopathy diagnosis, (ii) early cardiomyopathic traits, or (iii) gene-positive/phenotype-negative (G + P −) status. Sixteen adolescents (0.6%) met inclusion criteria, and 3 (18.8%) were G + (MYBPC3, MYH7, ACTC1). One in five relatives ( n = 13/71, 18.3%; 95% CI 11.0–28.9%) were referred, most having an abnormal ECG (12.7%). Nine relatives (12.7%; 95% CI 4.9–20.4%) exhibited early cardiomyopathy traits at baseline. One (1.4%) relative was G + /P − . Cardiomyopathy was diagnosed in 3 (4.2%, 95% CI 0.9–11.8%) relatives at baseline ( n = 2 HCM, n = 1 DCM). One relative with early cardiomyopathy traits underwent phenoconversion (NDLVC) during follow-up at 77 months, yielding an overall diagnostic rate of 5.6% (95% CI 2.0–13.8%) in 4 unrelated families. A joint clinical-genetic approach enabled personalized surveillance in 6 relatives (8.5%), including 2 (2.8%) diagnoses that would otherwise have been missed with conventional clinical screening. Conclusion : One in five relatives of ECG‑positive phenotype‑negative adolescents received a cardiomyopathy diagnosis or had early cardiomyopathy traits. A joint clinical-genetic approach in this subgroup may aid early cardiomyopathy detection in selected families, though findings remain exploratory and require validation in larger cohorts. What is Known – What is New: •Resting ECG can identify individuals harboring conditions linked to sudden cardiac death •The penetrance of cardiomyopathy is age dependent, which explains why screened adolescents may exhibit abnormal ECG patterns in the absence of a cardiomyopathy diagnosis •Our data indicate that extending screening to relatives of ECG-positive, phenotype-negative adolescents is justified, with one in five relatives receiving a new cardiomyopathy diagnosis (5.6%) or exhibiting early cardiomyopathy traits (11.3%) •A joint clinical/genetic evaluation in this context may help personalize screening strategies