Open AccessVariable and Severe Phenotypic Expression of the “Lebanese Allele” in Two Sisters with Familial Hypercholesterolemia
Author(s) -
Johnny Chahine,
Sarah Kreykes,
Jeremy Van’t Hof,
Daniel Duprez,
Prabhjot S. Nijjar
Publication year - 2021
Publication title -
vascular health and risk management
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.892
H-Index - 68
eISSN - 1178-2048
pISSN - 1176-6344
DOI - 10.2147/vhrm.s314704
Subject(s) - familial hypercholesterolemia , allele , ldl receptor , compound heterozygosity , phenotype , heterozygote advantage , genetics , medicine , allele frequency , endocrinology , lipoprotein , cholesterol , biology , gene
The "Lebanese allele" { LDLR c.2043 C>A (p.cys681X)} is a nonsense mutation in the low-density lipoprotein receptor ( LDLR ) gene that results in a truncated non-functioning LDLR protein. We report two sisters of Lebanese descent who presented with familial hypercholesterolemia (FH) and were both heterozygous for the Lebanese allele, but had very distinct LDL-C levels and clinical phenotypes. Whereas one of the sisters had LDL-C in the expected range of Heterozygous FH (HeFH) with the Lebanese allele (LDL-C of 292 mg/dl), the other sister had a more severe LDL-C phenotype in the Homozygous FH (HoFH) range (LDL-C of 520 mg/dl) along with manifest atherosclerosis. Surprisingly, she did not demonstrate a compound heterozygote or double heterozygote status. We discuss different mechanisms that are purported to play a role in modifying the phenotype of FH, including different variants and polygenic modifiers. HeFH patients with the Lebanese allele can have a wide spectrum of LDL-C levels that range from the typical heterozygous to homozygous phenotypes.