Key result
Screening identifies definite ARVC in ~23% of gene-elusive proband relatives.
Why the study?
Current guidelines recommend regular screening for first-degree relatives of gene-elusive ARVC patients similarly to genotype-positive relatives, but the multifactorial nature of gene-elusive ARVC may necessitate a different approach.
Does regular cardiac screening yield new ARVC diagnoses in first-degree relatives of ARVC probands without a validated genetic cause?
Cohort (n=44)
Yes
Does regular cardiac screening yield new ARVC diagnoses in first-degree relatives of ARVC probands without a validated genetic cause?
First-degree relatives of ARVC patients without a validated genetic cause show a substantial yield for ARVC diagnosis upon serial screening, supporting current guidelines that recommend longitudinal evaluation.
Supports serial screening in gene-elusive ARVC families; extends observational data aligning with current guidelines.
BACKGROUND: Current guidelines recommend regular screening for first-degree relatives of gene-elusive arrhythmogenic right ventricular cardiomyopathy (ARVC) patients using a similar regimen as for genotype-positive/phenotype-negative relatives. However, the multifactorial nature of gene-elusive ARVC may necessitate a different approach. This study aimed to determine the yield of cardiac screening in first-degree relatives of ARVC probands without a validated genetic cause. METHODS: We included all first-degree relatives of probands who (1) met the 2010 Task Force Criteria, (2) underwent next-generation sequencing that included all genes with at least moderate evidence for ARVC causation per Clinical Genome Resource appraisal (validated ARVC genes), and (3) had no pathogenic/likely pathogenic (P/LP) variants identified in these genes. The primary and secondary end points were definite ARVC by the 2010 Task Force Criteria and ventricular arrhythmia, respectively. RESULTS: ). Overall, 10 (23%) relatives had definite ARVC at baseline evaluation. Of the 20 relatives without definite ARVC who had follow-up available, 8/20 (40%) relatives progressed to definite ARVC during 9.0 (5.8-14.4) years of follow-up. No statistical difference in the yield of baseline screening or serial evaluation between relatives from families with a P/LP variant and relatives from families without a P/LP variant was observed. Of the 27 relatives who had follow-up available, ventricular arrhythmia was observed in 2/27 (7%) relatives and occurred 6.3 and 13.8 years after definite ARVC diagnosis. Both of those relatives were from families without a P/LP variant. CONCLUSIONS: These findings highlight the importance of managing first-degree relatives of ARVC probands without a validated genetic cause similarly to genotype-positive ARVC relatives. Furthermore, using a broad cardiomyopathy and arrhythmia gene panel in ARVC probands, rather than limiting testing to validated ARVC genes alone, is warranted.
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Muller et al. (2026) conducted a cohort in Arrhythmogenic right ventricular cardiomyopathy (n=44). Family screening for ARVC was evaluated on Definite ARVC by the 2010 Task Force Criteria at baseline evaluation. Among first-degree relatives of gene-elusive ARVC probands, family screening identified definite ARVC in 23% at baseline, and 40% of those initially unaffected progressed to ARVC over 9 years.
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