DOI: 10.1161/circep.125.014420 ISSN: 1941-3149

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

Steven A. Muller, Brittney Murray, Crystal Tichnell, Arman Salavati, Peter Loh, Richard T. Carrick, Moniek Cox, Pim van der Harst, Maarten J. Cramer, Marish I.F.J. Oerlemans, Alessio Gasperetti, Babken Asatryan, Stefan Zimmerman, J. Peter van Tintelen, Hugh Calkins, Cynthia A. James, Anneline S.J.M. te Riele
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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.

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