Yield of Family Screening in Arrhythmogenic Right Ventricular Cardiomyopathy Without a Validated Genetic Cause

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: We included 44 relatives (39.0 [22.3-45.8] years; 36% male) from 24 families. In 4 (17%) families, a P/LP variant was identified in a different cardiomyopathy/arrhythmia gene (SCN5A, LMNA, CDH2, FLNC). 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.