Abstract
PurposeLarge-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. MethodsThe Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. ResultsVia genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. ConclusionGenotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.
Highlights
With the plummeting costs of exome (ES) and genome sequencing (GS), the collection of high-coverage genomic data is increasingly becoming routine in genetic research
Familial hypercholesterolemia (FH) and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant
Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management
Summary
With the plummeting costs of exome (ES) and genome sequencing (GS), the collection of high-coverage genomic data is increasingly becoming routine in genetic research. 1234567890():,; Europe4) and having actionable treatment options.[5] FH, which primarily results from deleterious variants in the LDLR, APOB, or PCSK9 genes, involves the dysfunction of the lowdensity lipoprotein (LDL) receptor and concomitant overactivity of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, resulting in elevated low-density lipoprotein cholesterol (LDL-C) levels and a substantially increased risk of premature coronary heart disease (CHD).[6,7] While severely high LDL-C concentrations (>4.9 mmol/L) are commonly acknowledged in clinical FH diagnosis, recent studies highlight that FH-associated variant carriers display a wide spectrum of LDL-C levels, and the risk for CHD persists across the range of these values.[8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
