A case of autosomal recessive hypercholesterolemia with a novel mutation in the LDLRAP1 gene.

Abstract

Familial hypercholesterolemia (FH, OMIM number #143890), a life-threatening monogenic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C), is classified into dominant and recessive types (1). The dominant form of FH may result from mutations in the LDLR, APOB, and PCSK9 genes (2). However, mutations in the low-density lipoprotein receptor (LDLR) adaptor protein-1 (LDLRAP1) gene cause an autosomal recessive inheritance pattern of FH called autosomal recessive hypercholesterolemia (ARH, OMIM number #603813). The LDLRAP1 protein, encoded by the LDLRAP1 gene, is required for receptor-mediated endocytosis of LDL-C (2). ARH is a rare disorder with an estimated prevalence of less than 1 in a population of one million. This disease is considered a phenocopy of the most severe form of FH, homozygous familial hypercholesterolemia (HoFH; OMIM number 143890). Hence, most ARH patients are clinically indiscernible from HoFH, which is caused by two defective LDLR genes with an approximate prevalence of one individual per million (8). Considering that ARH patients may develop aggressive and premature atherosclerotic cardiovascular disease (ASCVD) due to hypercholesterolemia during early adulthood, lipid-lowering therapy must be initiated during childhood (3). Early identification of ARH patients through genetic analysis of the proband and their relatives can provide prognosis and subsequently appropriate, timely treatment. In this report, we describe a novel variant, c.649G>T, p.Glu217Ter, in the homozygous state in exon 7 of the LDLRAP1 gene, causing severe ARH.