Genetic and molecular basis of sudden cardiac death syndromes
Creators: name: Greiner, Alexander Michael
Publisher: name: University of Iowa
Year: 2025
Subjects: Medicine
public abstract

description: Sudden cardiac death (SCD) is responsible for over 400,000 deaths per year in the United States. While ischemic conditions cause the majority of SCD, non-ischemic etiologies of SCD comprise a sizable number of SCD cases. Non-ischemic SCD is often precipitated by the incitement of lethal tachyarrhythmias resulting from dysregulation of cardiac electrophysiology or structural abnormalities. These arrhythmic and cardiomyopathic forms of SCD are heritable in most cases; mutations in cardiac ion channels, ion channel interacting proteins, or cardiac metabolic proteins have been identified over the past three decades to underlie the major heritable forms of sudden cardiac death. While initially only useful for diagnosis and scientific hypothesis generation, genotype is becoming an ever-increasing part of the treatment plan for a patient. For example, Long QT Syndrome (LQT) patients receive either a beta-blocking or sodium channel-blocking agent depending on their genotype. Thus, understanding the genetic underpinnings of each SCD syndrome is important. While much has been discovered about the genetic underpinnings of SCD syndromes, current clinical and genetic technologies are only able to provide genetic diagnosis in 30% to 70% of cases, de- pending on the disease studied. We have taken large multigenerational families with known SCD syndromes, but no diagnostic results from clinical genetic testing, and have performed whole exome sequencing (WES), among other sequencing technologies, to further understand the genetic contribution to disease in each family.
description: We identified a large multigenerational family with SCD in five generations. A concerning number of premature ventricular contractions, PVCs, were identified in the proband of this family and her two daughters. More interesting was the discovery of idiopathic cardiac fibrosis in one daughter, and bicuspid aortic valve in two siblings of the proband. WES identified a variant in muscle segment homeobox 1, MSX1;c.405G&gt;C;p.E135D, which lies in a consensus SUMOylation sequence within the protein. Molecular studies suggest this mutation disrupts SUMOylation of MSX1 and disrupts previously reported protein-protein interactions with the TBX-family transcription factors TBX3 and TBX5. Early mouse studies suggest deletion of MSX1 is pro-arrhythmic and causes increases in mRNA levels of pro-fibrotic genes.
description: Brugada Syndrome (BrS) is a SCD syndrome and the leading cause of SCD in persons with structurally normal hearts. Mutation in the main cardiac sodium channel, SCN5A, contributes to 20% of cases. Over the past decades a number of minor disease-causing genes, including GPD1L, have been reported to cause approximately 10% of BrS cases. Approximately 70% of BrS cases lack an identifiable genetic cause. Recent efforts in the field to refine gene-disease criteria have suggested SCN5A is the only BrS-causing gene. We demonstrate that in a large multigenerational family with BrS that our identified mutation, GPD1L-A280V, is the only plausible disease causing gene in this family, but is potentiated by previously-reported risk single nucleotide polymorphisms.
description: Finally, we demonstrate preliminary evidence that variation in DEPDC5 and TTN may contribute to BrS and LQT, respectively. Ultimately, these studies provide new insight into SCD syndromes arising from variation in multiple genes, and provides a putative disease mechanism for one family through disruption of transcription factor protein-protein interaction.