+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Arteriosclerosis Thrombosis and Vascular Biology 33(12): 2909-2914

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 053120909

Download citation: RISBibTeXText

PMID: 24072694

DOI: 10.1161/atvbaha.113.302426

Related references

Comparison of clinical parameters with whole exome sequencing analysis results of autosomal recessive patients; a center experience. Molecular Biology Reports 46(1): 287-299, 2019

Exome sequencing identifies compound heterozygous PKHD1 mutations as a cause of autosomal recessive polycystic kidney disease. Chinese Medical Journal 125(14): 2482-2486, 2012

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease. Clinical Genetics 93(3): 603-612, 2018

Clinical application of whole-exome sequencing: a novel autosomal recessive spastic ataxia of Charlevoix-Saguenay sequence variation in a child with ataxia. JAMA Neurology 70(6): 788-791, 2013

Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family. British Journal of Dermatology 172(5): 1407-1411, 2015

The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis. Clinical Genetics 92(1): 80-85, 2017

Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy. American Journal of Human Genetics 94(4): 625-633, 2014

Impact of whole exome sequencing among Iranian patients with autosomal recessive retinitis pigmentosa. Archives of Iranian Medicine 18(11): 776-785, 2015

Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa. Human Molecular Genetics 27(4): 614-624, 2018

Whole-exome sequencing identifies novel autosomal recessive DSG1 mutations associated with mild SAM syndrome. British Journal of Dermatology 174(2): 444-448, 2016

Whole exome sequencing reveals novel EYS mutations in Chinese patients with autosomal recessive retinitis pigmentosa. Molecular Vision 25: 35-46, 2019

Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient. Bmc Neurology 14: 5, 2014

Whole-exome sequencing revealed HKDC1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa. Human Molecular Genetics 27(23): 4157-4168, 2018

Exome sequencing identifies a mutation in TMC1 as a novel cause of autosomal recessive nonsyndromic hearing loss. Journal of Translational Medicine 14: 29, 2016

Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing. Prenatal Diagnosis 38(1): 33-43, 2018