Clinico-pathological & genetic analysis of sudden cardiac death in the young

Abstract

Sudden cardiac death (SCD) is defined as sudden unexpected death occurring within one hour of onset of symptoms in an individual with or without pre-existing heart disease. The main hypothesis underlying this PhD thesis was that inherited heart diseases are responsible for a significant number of SCD in the young, including those in which the heart appears completely “normal” at postmortem (i.e. “sudden unexplained death or SUD”). Postmortem genetic studies, specifically an exome sequencing based molecular autopsy, will offer a comprehensive analysis of cardiac disease-related genes in SUD cases and families. Exome sequencing in a subgroup of 28 SUD cases (aged 1 to 40 years) revealed 3 rare variations in the common LQTS genes and 6 rare variations in an additional 25 common genes of cardiac arrhythmias and cardiomyopathies. Further, whole exome sequencing performed in a multigenerational family with two SUD cases, subtle post-mortem abnormalities and 12-lead ECG abnormalities identified two rare missense variants in non-cardiac genes and a novel missense variant in a cardiomyopathy-associated mitochondrial gene. These variants needs to be further evaluated by screening additional family members, tissue expression and functional studies. Probands seen at a multidisciplinary cardiac genetic clinic with a reported pathogenic mutation or variants of uncertain significance were further reviewed for any single nucleotide variant (SNV) reclassification by a blinded analysis. Five variants in six hypertrophic cardiomyopathy probands and four variants in probands with other inherited heart conditions were reclassified. In summary, exome based molecular autopsy ensures a comprehensive review of cardiac genes, has an increased likelihood of identifying pathogenic gene mutations including novel genes that may be associated with cardiac disease and sudden death. Periodic reassessment of SNV data is vital in all inherited cardiac disorders.