Variable and Severe Phenotypic Expression of the “Lebanese Allele” in Two Sisters with Familial Hypercholesterolemia

Abstract

Johnny Chahine, Sarah Kreykes, Jeremy R Van’t Hof, Daniel Duprez, Prabhjot Nijjar Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USACorrespondence: Prabhjot NijjarUniversity of Minnesota Medical School, 420 Delaware Street SE, MMC 508, Minneapolis, MN, 55455, USATel [phone]Fax [phone]Email [email protected]: 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.Keywords: familial hypercholesterolemia, familial hyperlipidemia, heterozygous, Lebanese allele

Keywords

• familial hypercholesterolemia
• familial hyperlipidemia
• heterozygous
• lebanese allele