LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

Christine L H Snozek, Susan A. Lagerstedt, Teck K. Khoo, Melvyn Rubenfire, William L. Isley, Laura J. Train, Linnea M. Baudhuin

Research output: Contribution to journalArticle

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Abstract

Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C>T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH.

Original languageEnglish (US)
Pages (from-to)85-90
Number of pages6
JournalEuropean Journal of Human Genetics
Volume17
Issue number1
DOIs
StatePublished - 2009

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Hyperlipoproteinemia Type II
LDL Receptors
Exons
Chromosomes
Phenotype
Mutation
LDL Cholesterol
Therapeutics
Genetic Testing
Angina Pectoris
Missense Mutation
African Americans
Stents
Coronary Vessels
Cardiovascular Diseases
Alleles
Myocardial Infarction
Lipids

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance. / Snozek, Christine L H; Lagerstedt, Susan A.; Khoo, Teck K.; Rubenfire, Melvyn; Isley, William L.; Train, Laura J.; Baudhuin, Linnea M.

In: European Journal of Human Genetics, Vol. 17, No. 1, 2009, p. 85-90.

Research output: Contribution to journalArticle

Snozek, Christine L H ; Lagerstedt, Susan A. ; Khoo, Teck K. ; Rubenfire, Melvyn ; Isley, William L. ; Train, Laura J. ; Baudhuin, Linnea M. / LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance. In: European Journal of Human Genetics. 2009 ; Vol. 17, No. 1. pp. 85-90.
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abstract = "Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C>T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH.",
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