Carson, Jason Christopher
(2020)
Enrichment for rare pathogenic and highly damaging variants in congenital heart disease patients.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Congenital heart disease (CHD), defined as any structural abnormality of the heart or great vessels, is a leading cause of morbidity and mortality in infants and young children. Even as survival rates for the most severe forms of CHD improve, patients still face a lifetime of monitoring, diagnostic procedures, and possible additional surgeries to address these defects or related issues. Compounding matters is recent evidence suggesting CHD patients may have an increased lifetime risk of developing cancer either due to some of the same genetic mutations that caused the CHD or as a result of other extrinsic factors such as repeated exposure to radiation during diagnostic or interventional procedures. The genetic etiology of CHD is quite complex with both sporadic and familial forms as well as monogenic forms with simple Mendelian inheritance and multigenic forms with complex inheritance patterns. This study investigated whether CHD patients have an increased burden of rare pathogenic or highly damaging variants in genes known to be associated with congenital heart defects or cancer. My results indicate pathogenic and highly damaging variants in some genes with a known association with CHD, but not in genes associated with cancer play a role in the etiology of heart development. Furthermore, these results appear to be consistent with a complex multigenic model of CHD. Finally, they suggest that variants in genes related to response to oxygen levels may serve as a prognostic indicator. However, this study has several limitations, the most notable being a nonrandom sample population and a lack of control for population substructure. In spite of these limitations, I feel that this research provides a good foundation on which to base future more in-depth analyses with more statistical power. This research is of public health importance as it can help shed light on the genetic etiology of CHD and provide insight into which patients may be at greater risk for later complications which in turn could lead to improved diagnostics, treatment, and preventative measures.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 July 2020 |
| Date Type: |
Publication |
| Defense Date: |
24 April 2020 |
| Approval Date: |
30 July 2020 |
| Submission Date: |
15 May 2020 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
204 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Congenital heart disease; Genetics, Enrichment analysis |
| Date Deposited: |
30 Jul 2020 21:17 |
| Last Modified: |
01 May 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39039 |
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