title: LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance.
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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Cardiovascular Laboratory Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Christine L H
authors.initials: CL
authors.lastname: Snozek
authors.forename: Susan A
authors.initials: SA
authors.lastname: Lagerstedt
authors.forename: Teck K
authors.initials: TK
authors.lastname: Khoo
authors.forename: Melvyn
authors.initials: M
authors.lastname: Rubenfire
authors.forename: William L
authors.initials: WL
authors.lastname: Isley
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Train
authors.forename: Linnea M
authors.initials: LM
authors.lastname: Baudhuin
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005091:Exons; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011401:Promoter Regions, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics; D015854:Up-Regulation
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases