Search

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic Introduction The complex diagnostic work up in SCA survivors often does not yield a concrete cardiological diagnosis. Moreover, there is conflicting evidence whether genetic testing could support or guide clinical diagnostics. Purpose To assess the molecular architecture of idiopathic ventricular fibrillation in cases without apparent evidence of specific structural or arrhythmic cardiac disease at initial diagnostic work up in a representative Czech cohort. Patients and Methods Between 2013 - 2020 we have ascertained 100 SCA survivors (54 M / 46 F; age range at cardiac arrest 5-69 years). Genetic counselling was followed by massively parallel DNA sequencing using custom-made panels comprising 100 cardiac conditions-related genes. Subsequently, thorough cardiological screening examinations in first degree relatives were carried out. Presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results Highly likely or certain molecular aetiology (i.e. based on the presence of Class 4 or 5 variants) was disclosed in 20/100 (20%) in PKP2 (3x), SCN5A (4x), RYR2 (3x), TTN (2x), PLN, FLNC, PRKAG2, KCNH2, KCNQ1, SLC4A, TNNT2, and DSP. Interestingly, the KCNE1 p.Asp85Asn (LQT 5 lite) variant, was detected in further 3/100 cases, representing a recognized risk factor for ventricular arrhythmias. Conclusions Genetic testing facilitates stratification of the cause of arrhythmia in a substantial portion of SCA survivors. The utility of positive outcomes of genetic testing was substantiated in 10/20 gene positive patients, where the genetic stratification led to diagnosis of concealed arrhythmogenic cardiomyopathy, whose extent of morphological changes was under the diagnostic sensibility of imaging modalities or ECG. Our results enable individualized care in SCA survivors and assure targeted preventive approaches in their relatives.

Funding Acknowledgements Supported by Ministry of Health of the Czech Republic, grant nr. NV18-02-00237. All rights reserved." Introduction "Molecular autopsy" in sudden cardiac death (SCD) is an important diagnostic tool for primary prevention of cardiac arrest in victim´s relatives and requires multicentric and multidisciplinary collaboration. Purpose To establish a national network for SCD diagnostics, to assess the acceptance of genetic testing in at risk relatives and to elucidate the genetic etiology of SCD in a representative Czech cohort aged below 45 years. Patients and Methods Between 2016 and 2019 we ascertained 70 SCD (50 M / 20 F), with positive family history for cardiac arrest in 8/70 cases. Only one family did not agree with molecular autopsy. Genetic counselling and cardiological screening examination was carried out in first degree relatives of SCD survivors accompanied by custom-made targeted panel massively parallel DNA sequencing comprising 100 cardiac conditions-related genes. Presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results According to post-mortem diagnosis most victims died of HCM (17/70), ACM (16/70), no structural heart disease was found in 15/70 cases, DCM/LVNC in 9/70, 6/70 were SIDS cases, other rare diagnoses comprised aortic dissection, or myocarditis. Most of victims died at sleep, only 9/70 victims died during strenuous activities. About 50% of SCD victims did not have cardiac complaints before death. Very likely or certain molecular etiology (i.e. based on presence of ACMG.net Class 4 to 5 variants) was disclosed in 12/70 (17%) in RYR2, FLNC, TTN, KCNH2 and KCNQ1 genes, whilst potentially causative DNA variants (Classes 3-4) were observed in 13/70 (18%) cases. In SIDS we did not find any pathogenic variants. Interestingly, the KCNE1 p.Asp85Asn (LQT 5 lite) variant, was detected in 3/70 cases as a recognized risk factor for ventricular arrhythmias. Conclusion The multidisciplinary cooperation in Czech Republic has been established, family survivors are willing to receive genetic and cardiological care, while centralised molecular genetic analysis enables reliable results which are in accordance with other multicentric studies. The molecular autopsy should, especially in SIDS, be expanded to whole exome sequencing.