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Yield of Family Screening in Arrhythmogenic Right Ventricular Cardiomyopathy Without a Validated Genetic Cause
Steven A Muller1,2,3, Brittney Murray1, Crystal Tichnell1
1Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (S.A.M., B.M., C.T., R.T.C., A.G., B.A., S.L.Z., H.C., C.A.J.).
Insights
First-degree relatives of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients without a genetic cause require similar cardiac screening as those with identified genetic mutations. Broad gene panel testing is recommended for comprehensive diagnosis and management.
Area of Science:
- Cardiology
- Genetics
- Clinical Medicine
Background:
- Current guidelines recommend genetic screening for first-degree relatives of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients.
- The multifactorial nature of gene-elusive ARVC may require a different screening approach.
- This study evaluated the efficacy of cardiac screening in first-degree relatives of ARVC probands lacking a confirmed genetic cause.
Purpose of the Study:
- To determine the diagnostic yield of cardiac screening in first-degree relatives of ARVC probands with no identified genetic cause.
- To compare screening outcomes between families with and without identified variants in other cardiomyopathy/arrhythmia genes.
- To inform management strategies for relatives of ARVC patients with unknown genetic etiology.
Main Methods:
- Included first-degree relatives of ARVC probands meeting 2010 Task Force Criteria.
- Utilized next-generation sequencing for validated ARVC genes.
- Assessed definite ARVC and ventricular arrhythmia as primary and secondary endpoints.
Main Results:
- 10 out of 44 relatives (23%) had definite ARVC at baseline.
- 40% (8/20) of relatives without baseline ARVC progressed to definite ARVC during follow-up.
- No significant difference in screening yield was observed between families with or without identified variants in other genes.
Conclusions:
- First-degree relatives of ARVC probands without a genetic cause should be managed similarly to genotype-positive relatives.
- Utilizing a broad cardiomyopathy and arrhythmia gene panel is recommended for ARVC probands.
- This approach enhances diagnostic accuracy and informs clinical management for families affected by ARVC.
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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