Biomaterial Database

Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia. 2023

Shirin Ibrahim, and Jeroen van Rooij, and Annemieke J M H Verkerk, and Jard de Vries, and Linda Zuurbier, and Joep Defesche, and Jorge Peter, and Willemijn A M Schonck, and Bahar Sedaghati-Khayat, and G Kees Hovingh, and André G Uitterlinden, and Erik S G Stroes, and Laurens F Reeskamp

Department of Vascular Medicine (S.I., J.P., W.A.M.S., G.K.H., E.S.G.S., L.F.R.), Amsterdam UMC, University of Amsterdam, the Netherlands.

Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH. An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%). The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.

UI	MeSH Term	Description	Entries
D008078	Cholesterol, LDL	Cholesterol which is contained in or bound to low density lipoproteins (LDL), including CHOLESTEROL ESTERS and free cholesterol.	LDL Cholesterol,Cholesteryl Linoleate, LDL,LDL Cholesteryl Linoleate,Low Density Lipoprotein Cholesterol,beta-Lipoprotein Cholesterol,Cholesterol, beta-Lipoprotein,beta Lipoprotein Cholesterol
D005838	Genotype	The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.	Genogroup,Genogroups,Genotypes
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006938	Hyperlipoproteinemia Type II	A group of familial disorders characterized by elevated circulating cholesterol contained in either LOW-DENSITY LIPOPROTEINS alone or also in VERY-LOW-DENSITY LIPOPROTEINS (pre-beta lipoproteins).	Hyperbetalipoproteinemia,Hypercholesterolemia, Essential,Hypercholesterolemia, Familial,Apolipoprotein B-100, Familial Defective,Apolipoprotein B-100, Familial Ligand-Defective,Familial Combined Hyperlipoproteinemia,Hyper-Low Density Lipoproteinemia,Hyper-Low-Density-Lipoproteinemia,Hyper-beta-Lipoproteinemia,Hypercholesterolemia, Autosomal Dominant,Hypercholesterolemia, Autosomal Dominant, Type B,Hypercholesterolemic Xanthomatosis, Familial,Hyperlipoproteinemia Type 2,Hyperlipoproteinemia Type IIa,Hyperlipoproteinemia Type IIb,Hyperlipoproteinemia, Type II,Hyperlipoproteinemia, Type IIa,LDL Receptor Disorder,Apolipoprotein B 100, Familial Defective,Apolipoprotein B 100, Familial Ligand Defective,Autosomal Dominant Hypercholesterolemia,Autosomal Dominant Hypercholesterolemias,Combined Hyperlipoproteinemia, Familial,Combined Hyperlipoproteinemias, Familial,Density Lipoproteinemia, Hyper-Low,Density Lipoproteinemias, Hyper-Low,Disorder, LDL Receptor,Disorders, LDL Receptor,Dominant Hypercholesterolemia, Autosomal,Dominant Hypercholesterolemias, Autosomal,Essential Hypercholesterolemia,Essential Hypercholesterolemias,Familial Combined Hyperlipoproteinemias,Familial Hypercholesterolemia,Familial Hypercholesterolemias,Familial Hypercholesterolemic Xanthomatoses,Familial Hypercholesterolemic Xanthomatosis,Hyper Low Density Lipoproteinemia,Hyper beta Lipoproteinemia,Hyper-Low Density Lipoproteinemias,Hyper-Low-Density-Lipoproteinemias,Hyper-beta-Lipoproteinemias,Hyperbetalipoproteinemias,Hypercholesterolemias, Autosomal Dominant,Hypercholesterolemias, Essential,Hypercholesterolemias, Familial,Hypercholesterolemic Xanthomatoses, Familial,Hyperlipoproteinemia Type 2s,Hyperlipoproteinemia Type IIas,Hyperlipoproteinemia Type IIbs,Hyperlipoproteinemia Type IIs,Hyperlipoproteinemia, Familial Combined,Hyperlipoproteinemias, Familial Combined,Hyperlipoproteinemias, Type II,Hyperlipoproteinemias, Type IIa,LDL Receptor Disorders,Lipoproteinemia, Hyper-Low Density,Lipoproteinemias, Hyper-Low Density,Receptor Disorder, LDL,Receptor Disorders, LDL,Type 2, Hyperlipoproteinemia,Type II Hyperlipoproteinemia,Type II Hyperlipoproteinemias,Type IIa Hyperlipoproteinemia,Type IIa Hyperlipoproteinemias,Xanthomatoses, Familial Hypercholesterolemic,Xanthomatosis, Familial Hypercholesterolemic
D000071449	Proprotein Convertase 9	A proprotein convertase that is essential for CHOLESTEROL homeostasis. It binds to and is required for the lysosomal degradation of the LDL RECEPTOR (LDLR); the VLDL receptor, and the APOLIPOPROTEIN E RECEPTOR. It also regulates neuronal APOPTOSIS.	NARC-1 Protein,Neural Apoptosis-Regulated Convertase 1,Proprotein Convertase, Subtilisin-Kexin Type 9,Convertase 9, Proprotein,NARC 1 Protein,Neural Apoptosis Regulated Convertase 1,Proprotein Convertase, Subtilisin Kexin Type 9
D014644	Genetic Variation	Genotypic differences observed among individuals in a population.	Genetic Diversity,Variation, Genetic,Diversity, Genetic,Diversities, Genetic,Genetic Diversities,Genetic Variations,Variations, Genetic
D056915	DNA Copy Number Variations	Stretches of genomic DNA that exist in different multiples between individuals. Many copy number variations have been associated with susceptibility or resistance to disease.	Copy Number Polymorphism,DNA Copy Number Variant,Copy Number Changes, DNA,Copy Number Polymorphisms,Copy Number Variants, DNA,Copy Number Variation, DNA,DNA Copy Number Change,DNA Copy Number Changes,DNA Copy Number Polymorphism,DNA Copy Number Polymorphisms,DNA Copy Number Variants,DNA Copy Number Variation,Polymorphism, Copy Number,Polymorphisms, Copy Number