Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants

Abstract

Background: Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening.

Methods: Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015-present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM.

Results: One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored DSP variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention.

Conclusions: Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in DSP-variant carriers and notably absent in PKP2-variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.

Keywords: arrhythmogenic right ventricular cardiomyopathy; desmosome; genetic screening; genomics; sudden cardiac death.

Figure 1.

Summary of postdisclosure clinical course for desmosome-variant carriers identified genomics-first through MyCode. ACM indicates arrhythmogenic cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; CMR, cardiac magnetic resonance; GC, genetic counselor; PCP, primary care provider; and TFC, task force criteria. *Denotes the 2 individuals with new cardiomyopathy diagnoses and implanted defibrillators.

Figure 2.

Number of patients (and percentage of 59 with follow-up) satisfying diagnostic criteria by group. A, Diagnostic arrhythmogenic right ventricular cardiomyopathy (ARVC) task force criteria groups, separated by major and minor criteria. B, Left-dominant criteria groups. Imaging findings included reduced ejection fraction or atypical late gadolinium enhancement in the left ventricle. Of note, the majority of arrhythmia findings (15/29; 52%) were in carriers with only other cardiac arrhythmias. ACM indicates arrhythmogenic cardiomyopathy; and Hx, history.

Figure 3.

Features of atypical late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging of 4 desmosome-variant carriers. Yellow arrowheads denote atypical LGE locations in the left ventricle (LV). A, Marked atypical LV LGE in the 57 y-old male DSP-variant carrier subsequently diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC). B, Septal midwall LGE in a 35 y-old male PKP2-variant carrier. C, Septal and anterior LGE in the subepicardium of a 72 y-old female DSP-variant carrier. Subendocardial enhancement in the inferior LV wall possibly due to prior infarct also visible (magenta arrowhead). D, Atypical midwall LGE in the basal to mid interventricular septum, as well as basal inferolateral segment in a 59 y-old female DSP-variant carrier.

Figure 4.

Distributions of arrhythmogenic right ventricular cardiomyopathy diagnostic categories according to the 2010 Task Force Criteria, modulated by the weight applied to the pathogenic/likely pathogenic variant.