You are here

Arterioscler Thromb Vasc Biol DOI:10.1161/ATVBAHA.113.302426

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

Publication TypeJournal Article
Year of Publication2013
AuthorsStitziel, NO, Fouchier, SW, Sjouke, B, Peloso, GM, Moscoso, AM, Auer, PL, Goel, A, Gigante, B, Barnes, TA, Melander, O, Orho-Melander, M, Duga, S, Sivapalaratnam, S, Nikpay, M, Martinelli, N, Girelli, D, Jackson, RD, Kooperberg, C, Lange, LA, Ardissino, D, McPherson, R, Farrall, M, Watkins, H, Reilly, MP, Rader, DJ, de Faire, U, Schunkert, H, Erdmann, J, Samani, NJ, Charnas, L, Altshuler, D, Gabriel, S, Kastelein, JJP, Defesche, JC, Nederveen, AJ, Kathiresan, S, G Hovingh, K
Corporate AuthorsNational Heart, Lung, and Blood Institute GO Exome Sequencing Project
JournalArterioscler Thromb Vasc Biol
Volume33
Issue12
Pages2909-14
Date Published2013 Dec
ISSN1524-4636
KeywordsAdult, Biomarkers, Cholesterol, Cholesterol Ester Storage Disease, Cholesterol, HDL, Cholesterol, LDL, DNA Mutational Analysis, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Heredity, Homozygote, Humans, Hypercholesterolemia, Linear Models, Liver, Male, Middle Aged, Mutation, Pedigree, Phenotype, Predictive Value of Tests, Principal Component Analysis, Sterol Esterase, Triglycerides, Young Adult
Abstract

OBJECTIVE: 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.

APPROACH AND RESULTS: 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.

CONCLUSIONS: 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.

URLhttp://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=24072694
DOI10.1161/ATVBAHA.113.302426
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24072694?dopt=Abstract

Alternate JournalArterioscler. Thromb. Vasc. Biol.
PubMed ID24072694
PubMed Central IDPMC4002172
Grant ListRC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
/ / British Heart Foundation / United Kingdom
UC2 HL103010 / HL / NHLBI NIH HHS / United States
R01 HL107816 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
K08 HL114642 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
UC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
K24 HL107643 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
K08-HL114642 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States