The emerging role of reassessment of genetic testing results in the diagnosis of the unexplained sudden cardiac arrest's causes

Abstract

Abstract Background The most common cause of Unexplained Sudden Cardiac Arrest (USCA) are hereditary primary arrhythmic syndromes and subclinical forms of cardiomyopathies. Both of them may be difficult to diagnose. Objective The aim of this study was to re-examine the role of genetic testing in patients after USCA during follow-up. Methods In the years 2014–2017 we studied 44 unrelated patients (pts) (23 men (53%), mean age 36 years) after USCA. All pts underwent cardiac evaluation including ECG, Holter, echo, coronary angiography, stress exercise test and, if necessary cardiac MRI and provocative drug testing. Standard diagnostic criteria were used according to currently available ESC guidelines. We performed next generation sequencing with panel covered coding regions of >4800 genes (26pts), 194 genes (5pts) and whole exome sequencing >2ehab724.3204 genes (5pts). Variants of frequency no greater than 0,001 in existing variants' databases and classified as damaging by at least 3 of applied software algorithms were assessed for pathogenicity according to ACMG standards. The enrolled patients were followed up. During the follow up, the classification of rare variants according to ACMG standards was repeated. Results Based on applicable standards and the clinical data collected, clinical diagnosis was made in 17 (39%) probands (Long QT Syndrome 21%, Brugada Syndrome 7%, Short QT Syndrome 7%, Early Repolarization Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia 2%, both). Genetic tests were performed in 36 pts. We identified 27 rare variants in 22 pts, in genes associated with inherited arrhythmia or cardiomyopathies, of these 23 rare variants were identified in years 2014–2017. The first classification was in 2017, then only 2 variants (in FLNC) were considered pathogenic and the remaining 21 were classified as Variants of Unknown Significance (VUS). During the years 2019–2021, 23 earlier identified rare variants were reclassified according to The American College of Medical Genetics and Genomics (ACMG) standards, of these 5 VUS became pathogenic/likely pathogenic variants. In addition, we performed genetic tests in next 5 pts – we identified 4 rare variants – 3 pathogenic and 1 VUS. Detection of certain hereditary background of SCA increased from 6,5% in years 2014–2017, to 25% in years 2019–2021. The median follow-up period was 2366 days (interquartile range 1785–2903 days). 17/44 (39%) pts had adequate discharge of ICD. Two pts were observed with reduction of left ventricular contractility and the development of the initial stages of dilated cardiomyopathy. Conclusion This study shows clinical utility of extensive clinical assessment and follow-up of patient after USCA. Routine genetic testing by next generation sequencing in the patients can help in diagnosis and re-evaluation of rare variants should be made during the follow-up. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): grant of National Institute of Cardiology, Warsaw, Poland