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Candidate gene study of familial pulmonary fibrosis

Sutton, Rachel M (2019) Candidate gene study of familial pulmonary fibrosis. Master's Thesis, University of Pittsburgh. (Unpublished)

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Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a progressively fatal interstitial lung disease (ILD) with no known cure. Pathogenic variants in the telomere maintenance and surfactant pathways have been implicated in both familial and sporadic IPF, although a significant fraction of familial IPF cases remain uncharacterized.
Methods: A panel of patients with clinical diagnoses of IPF were selected for whole genome sequencing (WGS) at the Simmons Center for Interstitial Lung Disease of UPMC. Selected patients had comorbid hematologic malignancies or family histories suggestive of familial disease. 25X WGS was performed and all candidate variants were verified by bi-directional sanger sequencing. Protein alignment was done for all candidate variants to determine the phylogenetic conservation. A three-generation pedigree was constructed for participants and included ages and health status of all family members, if known. Targeted questions related to associated malignancies of IPF and telomere mediated disease were additionally ascertained.
Results: Six patients underwent WGS, two patients have pending results. Patients included three women and three men ranging in age from 60 to 83 years old. Five patients had a family history consistent with familial pulmonary fibrosis and one patient had a comorbid hematologic malignancy (a myelodysplastic syndrome). Of the four patients sequenced, two patients were found to have exonic variants in the telomere maintenance genes RTEL1 and TERT. Two of the four patients who were familial by report had no known exonic variants suggesting the possibility of noncoding variants, potentially novel genes, or shared environmental exposures. The two patients, with results pending, have family histories that are consistent with familial disease and are concerning for telomere-related co-morbidities.
Conclusions: Future studies will require confirmation of these new variants through functional studies or testing segregation in affected families. As genetic variants associated with IPF continue to be identified and characterized, genetic counseling is likely to have an increasing place in the management of IPF patients and their families. Furthermore, studies like these will contribute to the growing body of literature and further impact the field of public health by improving clinical guidelines on the use of genetics in IPF management.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sutton, Rachel Mrms133@pitt.edurms133
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKass,
Committee MemberAlder,
Committee MemberGrubs,
Committee MemberMinster,
Date: 25 June 2019
Date Type: Publication
Defense Date: 10 April 2019
Approval Date: 25 June 2019
Submission Date: 2 April 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 65
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Genetic Counseling
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: idiopathic pulmonary fibrosis, IPF, familial IPF, genetics
Date Deposited: 25 Jun 2019 17:12
Last Modified: 25 Jun 2019 17:12


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