Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Clinical and molecular characterization of a cohort of patients evaluated due to CPVT.
G. Fernandez Ferro1, S. Scheiper-Welling2, J. P. Ochoa3, B. M. Beckmann2, T. Jenewein2, S. Kauferstein2
1Kardiologie, Health in Code, A Coruña, ES; 2Institute of Legal Medicine, Center of Sudden Death and Familiar Arrhythmiasyndroms, Goethe University of Frankfurt, University hospital, Frankfurt am Main; 3Kardiologie, Health in Code, A Coruña, Spanien;

BACKGROUND

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most lethal inherited arrhythmogenic diseases and it mainly affects the young, in the absence of structural heart disease.  This condition is difficult to diagnose and the first expression of disease can be an arrhythmic death. In the last years, genetic testing (GT) has become a useful tool in the challenging task of CPVT diagnosis. 

A diagnostic yield of the genetic study close to 60% has been reported, although it is highly variable and dependent on the phenotypic characteristics of the evaluated individuals.

PURPOSE

This study aimed to address the clinical characteristics and GT results in a cohort of individuals referred for genetic testing with a CPVT panel, in a real world-setting.

 

METHODS

This is a retrospective cohort study of patients, who were referred to CPVT panel evaluation. Only patients with available clinical information were included in the analysis. NGS genotyping was executed with a library of 251 genes, which contained the 12 genes included in the CPVT panel. NGS-based genomic testing was performed with classification of identified variants according to American College of Medical Genetics and Genomics guidelines. Patients were classified into two groups: those with clinically confirmed CPVT, defined as exercise-induced or emotional stress–induced bidirectional or polymorphic ventricular tachycardia in the setting of a structurally normal heart (Group 1), and those with clinical suspicion of CPVT, but who did not strictly meet the definitive diagnostic criteria for this disease (“Possible CPVT” according to current guidelines- Group 2).

RESULTS

n:128 unrelated patients were included in the analysis. Mean age at genetic testing was 36 y/o (±19), 47% were women and 18% had a familial history of sudden cardiac death. The diagnostic yield of the genetic study in the entire cohort was 50.7 %.  Analysis by clinical groups: Group 1 -  n:12. GT was positive in 67% (n:8), negative in 25% (n: 3) and inconclusive in 8% (n:1). 6/12 had pathogenic (P) or likely pathogenic (LP) variants in RYR2 and 2/12 in the KCNJ2 gene.  In Group 2 (n: 116), GT was positive in 49.1% (n=57), negative in 37.9% (n=44) and inconclusive in 12.9% (n=15).  We had identified P/LP variants in CPVT-related genes with definitive (RYR2, CASQ2) or disputed (KCNJ2) gene-disease validity in 40% of the referred patients: RYR2 (70.2%-n: 40), KCNJ2 (8.8%-n: 5), CASQ2 in homozygous/compound heterozygous carriers (3.5%-n: 2) (https://search.clinicalgenome.org/kb/conditions/MONDO:0017990). Relevant variants were also identified in other genes associated with channelopathies (SCN5A, 3.5%, n: 2 and KCNQ1, 1.7%, n: 1) and in genes associated with structural heart disease.

CONCLUSIONS

The diagnostic yield in patients referred for genetic testing for CPVT, was close to 51%. However, the yield increased up to 70% in those with clinically confirmed CPVT (Group 1). In this subgroup, all the positive results were due to genetic variants in CPVT related genes.  In the cohort of patients with non-definitive diagnosis of CPVT (Group 2), GT allowed confirmation of the suspicion of CPVT in 40% of the patients and, in addition, we were able to detect relevant genetic variants in other genes not associated with CPVT in 10% (differential diagnosis).


https://dgk.org/kongress_programme/jt2022/aV1397.html