Digital Theses Archive


Tesi etd-04012021-005154

Type of thesis
Genetics and molecular mechanisms of sudden cardiac death in the young
Scientific disciplinary sector
Istituto di Scienze della Vita - TRANSLATIONAL MEDICINE
relatore Prof. EMDIN, MICHELE
  • Sudden cardiac death
  • Molecular autopsy
  • Genetics
  • Next generation sequencing
  • Whole Exome Sequencing
Exam session start date
Sudden cardiac death (SCD) of the young has a major impact on society and devastating psycho-social effects on the family. In each individual patient, the underlying cardiac disorder can be known or asymptomatic and undiagnosed, so that SCD happens to be the first disease manifestation. Structural heart abnormalities, like cardiomyopathies, are responsible for the majority of SCDs in young people. However, a traditional forensic examination finds no apparent cause of death in 25-40% of cases, defined as sudden unexplained deaths (SUDs) and typically attributed to arrhythmogenic cardiac disease, such channelopathies. Either structural or arrhythmogenic conditions are usually inherited in autosomal dominant fashion. Molecular autopsy is the process of searching for a genetic cause of SCDs and it is particularly useful in SUDs where traditional autopsy is negative or only shows non-diagnostic features. Next Generation Sequencing (NGS) has disclosed the possibility of an “exome molecular autopsy”; nevertheless, only few genes, like in standard molecular autopsy, or limited panels tested, as in NGS studies, lead to a detection rate from 20% to 35%. Based on this evidence, this project aimed to perform whole exome sequencing (WES) on both retrospective and prospective cases of young SCD and SUD. The project also aimed to performed WES in patients diagnosed - on the bases of ECG, echocardiogram and cardiac magnetic resonance (CMR) - with ARVD, considering that is the cause of 1-14% of SCDs in the young and that about 40% of ARVD patients are left without a cause when variants in traditional desmosomal genes are searched for. The goals of the project are 1) to establish genotype-phenotype correlations, 2) to implement the flowcharts for molecular autopsy in SCD cases, 3) to increase the diagnostic yield in our cohort of ARVD patients. A specific approach using the broader gene list (at our knowledge) for variants filtration in SCD and ARVD cases and a preestablished scheme for variants pathogenicity interpretation - also merging exome data with autopsy/clinical diagnosis findings - has allowed to reach a high diagnostic yield (53.8%) for molecular autopsy, as well as for ARVD-patients (100%). Overall, 26 putative pathogenic variants were identified in 14/26 SCDs and 11 likely causal variants in 11/11 ARVD patients. These results suggest WES as powerful tool to help unveil the genetic substrate of SCD, that emerging as complex disease where multiple genetic variants may cumulatively contribute to its manifestations, and as a useful technique to investigating the genetic basis of ARVD. Moreover, NGS approach offers the possibility to store data for future reassessments which may unveil novel genotype-phenotype associations, thus supporting an extensive use of this approach.