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Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2909-14. doi: 10.1161/ATVBAHA.113.302426. Epub 2013 Sep 26.

Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia.

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From the Cardiovascular Division, Department of Medicine (N.O.S.) and Division of Statistical Genomics (N.O.S.), Washington University School of Medicine, Saint Louis, MO; Department of Vascular Medicine (B.S., S.S., J.J.P.K., G.K.H.) Department of Experimental Vascular Medicine (S.W.F., J.C.D), and Radiology (A.J.N.), Academic Medical Center, Amsterdam, The Netherlands; Center for Human Genetic Research, Boston, MA (G.M.P., A.M.M., D.A., S.K.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.M.P., A.M.M., D.A., S.K.); Fred Hutchinson Cancer Research Center, Seattle, WA (P.L.A., C.K.); Wellcome Trust Centre for Human Genetics (A.G., M.F., H.W.) and Cardiovascular Medicine, Radcliffe Department of Medicine (A.G., M.F., H.W.), University of Oxford, Oxford, United Kingdom; Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (B.G., U.d.F.); Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (T.A.B., N.J.S.); Department of Clinical Sciences, Hypertension and Cardiovascular Diseases (O.M.) and Diabetes and Cardiovascular Disease Genetic Epidemiology (M.O.-M.), Skania University Hospital, Lund University, Malmö, Sweden; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy (S.D.); Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.N.); Department of Medicine, University of Verona, Verona, Italy (N.M., D.G.); Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus (R.D.J.); Departments of Epidemiology, Genetics and Biostatistics, Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill (L.A.L.); Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy (D.A.); The John & Jennif



Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family.


We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance.


By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.


genetics; hypercholesterolemia; myocardial infarction

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