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Estimating the Prevalence of HHT Using Variant Effect Predictions

White, Carter (2024) Estimating the Prevalence of HHT Using Variant Effect Predictions. Master Essay, University of Pittsburgh.

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Hereditary Hemorrhagic Telangiectasia (HHT) is currently classified as a rare genetic condition that is characterized by potentially fatal blood vessel malformations. Upwards of 90% of HHT cases are caused by a pathogenic genetic variant in the ENG or ACVRL1 gene. Current estimates, based on case counting methods, calculate the prevalence of HHT to be between 1 in 5,000 and 1 in 10,000 people worldwide (0.01% - 0.02%). Due to variable HHT symptom presentation and severity, along with physician unfamiliarity, HHT is likely underdiagnosed by providers and therefore past prevalence measures may be inaccurate. In this study I (1) gathered variant data from gnomAD, (2) predicted variant pathogenicity using a variant effect predictor (VEP) from Ensembl, and (3) calculated the prevalence of HHT pathogenic variants at different levels of restrictiveness using allele frequencies. Without excluding any variants from the VEP software, a prevalence of 2.75% was calculated. After adjusting for homozygous variants, variants with large individual allele frequencies, and variants reliably labeled benign via clinical observations, a prevalence of 0.3203% was calculated. Finally, I adjusted the calculation for all clinically benign variant annotations. The calculated prevalence of HHT is then 0.2945%, 14.7-fold higher than currently accepted values. While there are notable limitations to the variant database, VEP, and datapoints used, an increased prevalence value holds great public health significance for the HHT and medical communities. This increased prevalence estimate suggests that HHT may indeed be more common in the population than currently reported.


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Item Type: Other Thesis, Dissertation, or Long Paper (Master Essay)
Status: Unpublished
CreatorsEmailPitt UsernameORCID
White, Cartercaw274@pitt.educaw2740009-0009-2377-8556
ContributionContributors NameEmailPitt UsernameORCID
Committee ChairRoman, Bethromanb@pitt.eduromanbUNSPECIFIED
Committee MemberMartinson, Jeremyjmartins@pitt.edujmartinsUNSPECIFIED
Committee MemberAnzell, Anthonyara126@pitt.eduara126UNSPECIFIED
Date: 3 January 2024
Date Type: Completion
Submission Date: 14 December 2023
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 62
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MPH - Master of Public Health
Thesis Type: Master Essay
Refereed: Yes
Uncontrolled Keywords: HHT, Prevalence, Genetic, Variant, Genetic Variant Analysis, ENG, ACVRL1, ALK1, VEP, Variant Effect Predictor, GnomAD, Ensembl, Hereditary Hemorrhagic Telangiectasia, Rare disease, SIFT, PolyPhen, CADD
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Date Deposited: 03 Jan 2024 17:52
Last Modified: 03 Jan 2024 17:52


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