Jian Wang1, Jacqueline S Dron1, Matthew R Ban1, John F Robinson1, Adam D McIntyre1, Maher Alazzam1, Pei Jun Zhao1, Allison A Dilliott1, Henian Cao1, Murray W Huff1, David Rhainds1, Cécile Low-Kam1, Marie-Pierre Dubé1, Guillaume Lettre1, Jean-Claude Tardif1, Robert A Hegele2. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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). CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH AND RESULTS: 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). CONCLUSIONS: 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: Michael A Iacocca; Joana R Chora; Alain Carrié; Tomáš Freiberger; Sarah E Leigh; Joep C Defesche; C Lisa Kurtz; Marina T DiStefano; Raul D Santos; Steve E Humphries; Pedro Mata; Cinthia E Jannes; Amanda J Hooper; Katherine A Wilemon; Pascale Benlian; Robert O'Connor; John Garcia; Hannah Wand; Lukáš Tichy; Eric J Sijbrands; Robert A Hegele; Mafalda Bourbon; Joshua W Knowles Journal: Hum Mutat Date: 2018-11 Impact factor: 4.878
Authors: Abhimanyu Garg; Sergio Fazio; P Barton Duell; Alexis Baass; Chandrasekhar Udata; Tenshang Joh; Tom Riel; Marina Sirota; Danielle Dettling; Hong Liang; Pamela D Garzone; Barry Gumbiner; Hong Wan Journal: J Endocr Soc Date: 2019-11-29