title: Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.
abstract: Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic.
  
  
  
  We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL).
  
  
  
  In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores.
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Dron
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ban
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: John F
authors.initials: JF
authors.lastname: Robinson
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Adam D
authors.initials: AD
authors.lastname: McIntyre
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Maher
authors.initials: M
authors.lastname: Alazzam
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Pei Jun
authors.initials: PJ
authors.lastname: Zhao
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Allison A
authors.initials: AA
authors.lastname: Dilliott
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: David
authors.initials: D
authors.lastname: Rhainds
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Cécile
authors.initials: C
authors.lastname: Low-Kam
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.). hegele@robarts.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D040941:Heredity; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009154:Mutation; D009864:Ontario; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; D005819:Genetic Markers
keywords: cholesterol, LDL; hypercholesterolemia type IIA; hyperlipoproteinemias; mutation; sequence analysis, DNA