Abstract
Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.
Highlights
Sudden death (SD) is a serious event that has a great socioeconomic impact on families and the community, and its incidence increases with age
There is a subgroup with autopsy findings of uncertain significance [12]. These include idiopathic left ventricular hypertrophy (LVH) in the absence of myocyte disarray or secondary causes [11,13,14]; coronary atherosclerosis (CA) without significant narrowing of the arterial lumen, defined as an obstruction inferior to 75% of the lumen of the vessel, along with no evidence of acute or chronic ischemia; primary myocardial fibrosis (PMF) without signs of structural or ischemic cardiopathy [11,14]. It is in these cases in which we aim to evaluate the usefulness of molecular autopsy to reach a precise diagnosis, considering that these findings of uncertain significance could be an innocent and coincidental finding, or part of an abnormal variant: physiological LVH in genetically predisposed individuals, or part of the HCM spectrum in the case of idiopathic LVH; or an ischemic trigger to unmask lethal arrhythmia of an underlying genetic cause in relation to nonsignificant CA and PMF [11,14]
57 were excluded following the exclusion criteria: 30 cases (34%) showed positive results for the toxicological screening; one case (1%) presented records of severe arterial hypertension as a secondary cause for LVH; 11 cases (13%) presented CA affecting more than 75% of the vessel lumen, and five cases (6%) were younger than 1 year old
Summary
Sudden death (SD) is a serious event that has a great socioeconomic impact on families and the community, and its incidence increases with age. Autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed
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