Recurrent acute myocarditis: An under-recognized clinical entity associated with the later diagnosis of a genetic arrhythmogenic cardiomyopathy.

Background: Myocardial inflammation has been consistently associated with genetic arrhythmogenic cardiomyopathy (ACM) and it has been hypothesized that episodes mimicking acute myocarditis (AM) could represent early inflammatory phases of the disease. Objective: We evaluated the temporal association between recurrent acute myocarditis (RAM) episodes and the later diagnosis of a genetic ACM. Materials and methods: Between January 2012 and December 2021, patients with RAM and no previous cardiomyopathy were included (Recurrent Acute Myocarditis Registry, NCT04589156). A follow-up visit including clinical evaluation, resting and stress electrocardiogram, cardiac magnetic resonance imaging, and genetic testing was carried out. Endpoints of the study was the incidence of both ACM diagnosis criteria and ACM genetic mutation at the end of follow-up. Results: Twenty-one patients with RAM were included and follow-up was completed in 19/21 patients (90%). At the end of follow-up, 3.3 ± 2.9 years after the last AM episode, 14/21 (67%) patients with an ACM phenotype (biventricular: 10/14, 71%; left ventricular: 4/14, 29%) underwent genetic testing. A pathogenic or likely pathogenic mutation was found in 8/14 patients (57%), 5/8 in the Desmoplakin gene, 2/8 in the Plakophillin-2 gene, and 1/8 in the Titin gene. Family history of cardiomyopathy or early sudden cardiac death had a positive predictive value of 88% for the presence of an underlying genetic mutation in patients with RAM. Conclusion: RAM is a rare entity associated with the latter diagnosis of an ACM genetic mutation in more than a third of the cases. In those patients, RAM episodes represent early inflammatory phases of the disease. Including RAM episodes in ACM diagnosis criteria might allow early diagnosis and potential therapeutic interventions.

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations.

Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.

Unusual clinical description of adult with Timothy syndrome, carrier of a new heterozygote mutation of CACNA1C.

CANAC1C encodes for the main cardiac L-type calcium channel and mutations on it lead to a prolonged QT interval in Timothy Syndrome (TS). We provide a new de novo constitutional heterozygote missense variation in CACNA1C in a living adult woman, also carrier of the known c.2146-1G>C heterozygous variation of PKP2 inherited from her father. To our knowledge, this patient is the first to have the two variations in these genes. Theses clinical and molecular findings expand the clinical and molecular spectrum of TS and show the interest of next generation sequencing or whole exome sequencing in rare disorders, atypical or novel phenotype.