510 GENETIC CHARACTERIZATION OF BIOPSY-PROVEN MYOCARDITIS: A PILOT STUDY
Authors: Marinas Maria Bueno , Baritussio Anna , Cason Marco , Celeghin Rudy , Giordani Andrea , Carturan Elisa , De Gaspari Monica , Rizzo Stefania , Tarantini Giuseppe , Marcolongo Renzo , Basso Cristina , Iliceto Sabino , Patrizia Caforio Alida Linda , Pilichou Kalliopi 
Published: December 2022

Genetic characterization of biopsy-proven myocarditis: a pilot study

Background

Myocarditis is characterized by the presence of an inflammatory infiltrate in the myocardium with degenerative/necrotic changes of cardiomyocytes, not-related to ischemic damage. Its clinical presentation is extremely heterogenous. Endomyocardial Biopsy (EMB) is the diagnostic gold standard and provides etiopathogenetic diagnosis. Biopsy-proven myocarditis may be infectious, mainly viral, toxic or non-infectious immune-mediated/autoimmune. A complex interplay between genetic factors, environmental triggers (i.e. viral infection) and the immune response of the host is postulated at the basis of different disease evolution.

Purpose

To determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy-related genes in a well-characterized cohort of biopsy-proven myocarditis.

Methods

Seventy-three biopsy-proven myocarditis-affected patients (mean age 51±9, 41 males) underwent screening of 200 genes related to inherited cardiomyopathies. Definite/moderate gene association with Dilated Cardiomyopathy (DCM) and Arrhythmogenic Cardiomyopathy was based on the ClinGen framework. Variant prioritization was carried out using American College of Medical Genetics and Genomics rules. Correlation with presence of virus on endomyocardial biopsy by polymerase chain reaction, family history and serum anti-heart autoantibodies (AHA) and/or aintiintercalated-disk autoantibodies (AIDA), among other clinical features, was appraised.

Results

Nineteen of the 73 biopsy-proven myocarditis patients (26%) carried a P/LP variant in cardiac-related genes. Titin (TTN) was the most overrepresented gene accounting for 11% of cases (8/73), followed by Myosin Binding Protein C3 (MYBPC3) and Desmoplakin (DSP), each accounting for 3% of cases (2/73), respectively. No differences were observed in the distribution of disease onset, heart failure classification (NYHA class), ejection fraction, presence of virus and presence of anti-heart autoantibodies between genotype-positive and genotype-negative cohorts. However, 12 of the 19 genotype-positive index cases (63%) referred family history for cardiomyopathy and/or sudden cardiac death; whereas only 4 of the 54 genotype-negative declared positive family history, demonstrating a statistically significant difference. On the other hand, 37% of genotype positive patients declared negative family history, suggesting a non-familial or sporadic form of myocarditis.

Conclusion

The prevalence of clinically actionable P/LP variants in cardiomyopathy-related genes is nearly one third of biopsy-proven viral or autoimmune myocarditis patients, most of them associated with DCM, but clinical parameters do not differ between genotype-positive and genotype-negative patients. On the other hand, positive family history in genotype-positive patients indicate that family history assessment is mandatory to identify the genetic substrate of inherited inflammatory cardiomyopathies.