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

Arterioscler Thromb Vasc Biol
Authors
Keywords
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.

Year of Publication
2013
Journal
Arterioscler Thromb Vasc Biol
Volume
33
Issue
12
Pages
2909-14
Date Published
2013 Dec
ISSN
1524-4636
URL
DOI
10.1161/ATVBAHA.113.302426
PubMed ID
24072694
PubMed Central ID
PMC4002172
Links
Grant list
RC2 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