Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia

Abstract

Purpose: Large-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.

Methods: The 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.

Results: Via 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.

Conclusion: 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.

Keywords: cascade screening; familial hypercholesterolemia; genomics-guided disease management; population-based biobank; recall by genotype.

Fig. 1

Overview of recall by genotype approach for familial hypercholesterolemia within the Estonian Genome Center and subsequent clinical management.

Fig. 2

Distribution of statin-adjusted LDL-C values in FH-associated variant carriers. (n = 41, mean LDL-C 5.78 mmol/L, SD 1.85) and noncarriers (n = 978, mean LDL-C 3.56 mmol/L, SD 0.98). The LDL-C level was increased by 2.33 mmol/L (SD 0.18) in individuals harboring an FH-associated variant, compared with noncarriers. FH familial hypercholesterolemia, LDL low-density lipoprotein.

Fig. 3

Subclinical atherosclerotic cardiovascular disease in FH-associated variant carriers. Coronary artery calcium (CAC) scores of familial hypercholesterolemia (FH)-associated variant carriers with subclinical disease and CAC >0. (n = 19) (filled colored circles) in comparison with the distribution of CAC scores in the Multi-Ethnic Study of Atherosclerosis (MESA) subcohort of Caucasian ethnicity and without symptomatic clinical atherosclerotic cardiovascular disease (ASCVD) and treated diabetes. The rectangles represent the expected CAC score distribution between the 25th and 75th percentile in the MESA subcohort for every age and for men (blue) and women (red) separately, with age on the x-axis and CAC score on the y-axis. While 16 individuals were not expected to have subclinical ASCVD, three individuals did (indicated with black circles). However, the 61-year-old female with LDLR p.Gly396Ala and the 54-year-old female with APOB p.Arg3527Gln displayed plaques in carotid arteries. The 59-year-old male harbored LDLR p.Arg115Cys.

Fig. 4

Clinical management of FH-associated variant carriers. (a) Disease diagnoses in familial hypercholesterolemia (FH)-associated variant carriers before and after the study. After clinical and imaging-based phenotyping, 37 participants were diagnosed with FH: 3 carried FH diagnosis before the study (crossed lines), 21 participants were reclassified from having nonspecific hypercholesterolemia to FH (left-leaning diagonal lines), and 13 were newly diagnosed cases (right-leaning diagonal lines). (b) Statin treatment in FH-associated variant carriers before and after the study. At the initial appointment, 13 (32%) participants reported statin use, while 28 (68%) did not. At the end of the study moderate-intensity statin treatment was started for 14 (34%), and up-titrated to or kept on high-intensity statin treatment for 13 (32%) carriers. Statin treatment was not started for 14 (34%) participants, including 8 who either had contraindications or declined.