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.

A Global Review on the Utility of Genetic Testing for Familial Hypercholesterolemia

“…Cascade screening was performed in 12 of the 21 studies, which occurred in Italy, Spain, Slovak Republic, India, Estonia, China, Vietnam, and Western Australia [28][29][30][31][32][33][34][35][36][37][38][39]. Among those 12 studies, the evidence suggested that first-degree relatives showed improved FH diagnosis and underwent treatment initiation, continued treatment, and/or treatment modification that resulted in improved LDL and total blood cholesterol.…”

“…Finally, more research is needed to examine and determine the role of non-clinical outcomes and PROs following FH genetic testing, identify resources needed to inform treatment goals and help improve treatment outcomes in FH patients, and assess clinical outcomes following FH genetic testing in non-Caucasian and pediatric populations in the US and abroad. [38] China [30] Setia et al [32] Pang et al [28] Abul-Husn et al [21] Jones et al [27] Wang et al [63] Wu et al [33] Truong et al [34] Rubio-Marín et al [36] Alver et al [39] Continued treatment 92.26…”

“…Amor-Salamanca et al [31] Setia et al [32] Pang et al [28] Abul-Husn et al [21] Jones et al [27] Gómez et al [64] Rubio-Marín et al [36] Alver et al [39] Modified treatment and/or dose 8.06…”

“…Sperlongano et al [30] Pang et al [28] Abul-Husn et al [21] Jones et al [27] Wang et al [63] Rubio-Marín et al [36] Improved total blood cholesterol levels 0.01 Sperlongano et al [30] Vohnout et al [29] Setia et al [32] Pang et al [28] Averna et al [60] Wu et al [33] Rubio-Marín et al [36] Alver et al [39] Genetic counseling 5. 63 Averna et al [60] Jones et al [27] None reported 86.…”

“… Clinical Outcome(s) Reported Among Populations Tested Percent of Total Clinically Suspected Individuals Tested ( n = 60,893) Citation Treatment initiation 92.68 Vohnout et al [ 29 ] Sperlongano et al [ 30 ] Setia et al [ 32 ] Pang et al [ 28 ] Abul-Husn et al [ 21 ] Jones et al [ 27 ] Wang et al [ 63 ] Wu et al [ 33 ] Truong et al [ 34 ] Rubio-Marín et al [ 36 ] Alver et al [ 39 ] Continued treatment 92.26 Amor-Salamanca et al [ 31 ] Setia et al [ 32 ] Pang et al [ 28 ] Abul-Husn et al [ 21 ] Jones et al [ 27 ] Gómez et al [ 64 ] Rubio-Marín et al [ 36 ] Alver et al [ 39 ] Modified treatment and/or dose 8.06 Jones et al [ 27 ] Rubio-Marín et al [ 36 ] Alver et al [ 39 ] Improved LDL cholesterol 84.00 Sperlongano et al [ 30 ] Pang et al [ 28 ] Abul-Husn et al [ 21 ] …”