Dissertation
Genetic and molecular basis of sudden cardiac death syndromes
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007095
Abstract
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.
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>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.
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.
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.
Details
- Title: Subtitle
- Genetic and molecular basis of sudden cardiac death syndromes
- Creators
- Alexander Michael Greiner
- Contributors
- Barry London (Advisor)Alexander Bassuk (Committee Member)Benjamin Darbro (Committee Member)Chad Grueter (Committee Member)Kaikobad Irani (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007095
- Publisher
- University of Iowa
- Number of pages
- xvii, 125 pages
- Copyright
- Copyright 2023 Alexander Michael Greiner
- Language
- English
- Date submitted
- 04/09/2023
- Date approved
- 06/30/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 107-125).
- Public Abstract (ETD)
- Sudden cardiac death (SCD) causes more than 350,000 deaths per year in the United States. SCD is defined as death of a cardiac origin which occurs within one hour of the onset of cardiovascular symptoms. While myocardial infarction, also known as a heart attack, is the leading cause of SCD, abnormal heart rhythms, arrhythmias, as well as abnormal heart muscle, cardiomyopathies, also cause SCD. Arrhythmias and cardiomyopathies are insidious forms of SCD, as individuals suffering from SCD from these conditions may have never had single cardiovascular symptom until they die. Clinical examination and testing is able to identify a number of patients at risk for SCD due to arrhythmias and cardiomyopathies. However, clinical signs of an arrhythmia, most often found on an electrocardiogram, may be variable and thus hidden from detection. The heritability of some SCD syndromes was known early on in their discovery. Improvements in DNA sequencing technologies, and the completion of the human genome project at the turn of the century, allowed for discovery of the genes containing mutations causing a portion of these SCD syndromes. Over the past two decades, an explosion of genes known to cause SCD has occurred. While knowing a gene mutation underlying a disease previously served a descriptive role, the same mutation today serves both a diagnostic, prognostic, and therapeutic role. Though an explosion of reported SCD genes has occurred, certain gene-disease associ- ations have recently come under scrutiny. The first part of this work focuses on one SCD syndrome, Brugada Syndrome (BrS), and my work to affirm that a mutation in a gene, GPD1L, causes BrS. The association between GPD1L and BrS is one of the gene-disease as- sociations which have recently come under scrutiny. Using multiple sequencing technologies, our data suggests that GPD1L is the only plausible mutation causing BrS in a large family we previously studied. ix Unfortunately, individuals and families with SCD can still have no known cause for their SCD syndrome, even after exhaustion of currently feasible clinical genetic testing. The sec- ond part of my works focuses on multigenerational families who have SCD syndromes but no identifiable genetic mutation which may underlie their disease. For two families, I hypothe- sized we could use whole-exome sequencing to detect single mutations which could underpin each families SCD syndrome. In the first family, we identify a mutation in a transcription factor, MSX1, and demonstrate that our identified mutation impacts interactions of this pro- tein with other transcription factors. This may underlie the sudden cardiac death phenotype in this family. In the second family, we identify a mutation in an epilepsy gene, DEPDC5, and show preliminary data which suggests DEPDC5 may contribute to BrS in this family. Lastly, the third and fourth families appeared late in my doctoral work and harbored trun- cating mutations in the large protein TTN and presented with Long QT Syndrome. For these families, I demonstrate proof-of-concept data for a technique which may be used to study previously-identified mutations in the family. Altogether, the studies herein demonstrate the power of combining sequencing studies and subsequent molecular biology investigations. Herein, our work suggests GPD1L remains a viable cause of BrS, MSX1 may underlie a complex SCD syndrome, DEPDC5 may contribute to BrS, and TTN may be implicated in Long QT Syndrome.
- Academic Unit
- Craniofacial Anomalies Research Center; Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984425315202771
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