Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies.

Campuzano O1,2,3,4, Fernandez-Falgueras A1, Sarquella-Brugada G2,5, Cesar S5, Arbelo E3,6, García-Álvarez A6, Jordà P6, Coll M1, Fiol V5, Iglesias A1,3, Perez-Serra A1,3, Mates J1, Del Olmo B1, Ferrer C1, Alcalde M1,3, Puigmulé M1, Mademont-Soler I1, Pico F1, Lopez L1, Tiron C7, Brugada J3,5,6, Brugada R1,2,3,7.

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Abstract

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.