Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results

Authors

Ozan Dikilitas
Alborz Sherafati
Seyedmohammad Saadatagah
Benjamin A Satterfield
David C Kochan
Katherine C Anderson
Wendy K Chung
Scott J Hebbring
Zachary M Salvati
Richard R Sharp
Amy C Sturm
Richard A Gibbs
Robb Rowley
Eric Venner
Jodell E Linder
Laney K Jones
Emma F Perez
Josh F Peterson
Gail P Jarvik
Heidi L Rehm
Hana Zouk
Dan M Roden
Marc S Williams
Teri A Manolio
Iftikhar J Kullo

Publication Date

4-1-2023

Journal

Circulation: Genomic and Precision Medicine

DOI

10.1161/CIRCGEN.122.003816

PMID

37071725

PMCID

PMC10113961

PubMedCentral® Posted Date

4-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

no

Keywords

Adult, Humans, Proprotein Convertase 9, Electronic Health Records, Penetrance, Cardiovascular Diseases, Prevalence, Prospective Studies, Risk Factors, Hyperlipoproteinemia Type II, Coronary Artery Disease, Heart Disease Risk Factors, Genomics

Abstract

BACKGROUND: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network.

METHODS: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including

RESULTS: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00-4.53]) and premature CHD (odds ratio, 3.68 [2.34-5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results.

CONCLUSIONS: In a multisite cohort of electronic health record-linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record-linked biobanks to detect FH.