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Enrichment for rare pathogenic and highly damaging variants in congenital heart disease patients

Carson, Jason Christopher (2020) Enrichment for rare pathogenic and highly damaging variants in congenital heart disease patients. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Carson, Jason Christopherjcc141@pitt.edujcc1410000-0003-1724-0492
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLo, Ceciliacel36@pitt.educel36
Committee MemberMinster, Ryanrminster@pitt.edurminster
Committee MemberKostka, Denniskostka@pitt.edukostka
Committee MemberPark, Hyun Junghyp15@pitt.eduhyp15
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: Graduate 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: 30 Jul 2020 21:17
URI: http://d-scholarship.pitt.edu/id/eprint/39039

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