Malena P. Pantou

Background: Homozygous truncating mutations located in the C-terminal region of the desmoplakin gene (DSP) are known to mainly cause Carvajal syndrome, an autosomal recessive syndromic form of arrhythmogenic cardiomyopathy with an extra-cardiac cutaneous phenotype. Case presentation: Here we describe a female proband with a documented arrhythmogenic left ventricular cardiomyopathy and a syncopal episode at the age of 13, who was found homozygous for the novel DSP variant: NM_004415.4:c.8586delC, p.(Ser2863Hisfs*20) at the extreme C-terminal region of the protein, just 8 amino acids upstream the stop codon. She did not have any of the typical dermatological symptoms that characterize Carvajal syndrome. Her brother had died suddenly at the age of 18 during exercise and was found homozygous for the same variant at the post-mortem, while their parents were heterozygous. The region of origin of both parents was the same geographic area of Greece, but they were not aware of any common ancestor. Detailed clinical examination revealed that the mother displayed a mild arrhythmic phenotype, while the father was asymptomatic. Conclusion: These observations pinpoint to a significant functional role of the extreme C-terminal tail of the protein.

Background: Myocarditis is increasingly associated with dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Purpose: The aim of our study was to define if a genetic predisposition exists in cases of myocarditis with suspicious findings of inherited cardiovascular disease (noise) in the family. Methods: Consecutive patients referred to our unit from 2010 to 2021, with a presentation of acute or clinically suspected myocarditis, as defined by current criteria, went through family screening of the first and second-degree relatives. Patients fulfilling typical criteria for definite ARVC upon presentation were excluded. Patients with suspicious familial findings (familial noise) including a. family history of sudden cardiac death, b. family history of myocarditis or cardiomyopathy or c. findings suggestive of cardiac disease in the relatives (ECG abnormalities, complex or frequent ventricular arrhythmias, conduction disease, troponemia, structural abnormalities suggestive of cardiomyopathy) went through genetic analysis for 90 genes associated with cardiomyopathy. Results: Fifty-five patients with myocarditis and familial noise were included (Table 1). In 49 (89%) patients ≥2 diagnostic criteria for clinically suspected myocarditis were fulfilled. In 50% of the patients, the noise in the family was revealed upon familial screening as there was no relevant family history. Myocardial inflammation was confirmed in 16 (29%) patients with histological findings on endomyocardial biopsy or ≥2 Lake Louise Criteria on cardiac magnetic resonance. Pathogenic or likely pathogenic variants were identified in 78% of the cases (figure 1). Desmoplakin (24%) followed by lamin A/C (13%) and titin (9%) were the most common genes identified. In cases with confirmed myocardial inflammation the genetic yield increased to 87%. Conclusions: A significant proportion of myocarditis patients with “familial noise” carry a pathogenic genetic variant in a cardiomyopathy related gene. These findings potentially affect the clinical management and need for family and genetic screening in patients with clinically suspected myocarditis. Funding Acknowledgement: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Greek Network for Precision Medicine in Cardiology and the Prevention of Sudden Cardiac Death in the Young, icardiacnet

Restrictive cardiomyopathy is a rare cardiac disease, for which several genes including TNNT2, MYPN, FLNC and TNNI3 have been associated with its familial form. Here we describe a female proband with a severely manifested restrictive phenotype leading to heart transplantation at the age of 41, who was found homozygous for the novel TNNI3 mutation: NM_000363.4:c.586G > C, p.(Asp196His). Her parents were third-degree cousins originating from a small village and although they were found heterozygous for the same variant they displayed no symptoms of the disease. Her older sister who was also found heterozygous was asymptomatic. Her twin sister and her brother who were homozygous for the same variant displayed a restrictive and a hypertrophic phenotype, respectively. Their children are all carriers of the mutation and remain asymptomatic until the age of 21. These observations point to a recessive mode of inheritance reported for the first time for this combination of gene/disease.