The first complete genotype- phenotype of Lebanese patients with Familial hypercholesterolemia -

Abstract

Familial hypercholesterolemia (FH) is an inherited disease that impairs the normal uptake and clearance of blood-LDL by the liver. FH is characterized by elevated serum LDL-C that deposits in tissues and arterial walls leading to premature cardiovascular disease. This deposition starts at early age, in childhood or even in infancy causing atherosclerosis, thus increases the risk of coronary heart disease. For many years, FH was thought of as a monogenetic disease caused by mutation in the LDL receptor, and over the past decade three new genes were shown to be implicated in FH fostering the polygenic nature of the disease. Advances in gene sequencing of clinically diagnosed FH patients allowed the identification of a genetic gap that is linked to the unexplained genotype-phenotype miss-correlation. We have been studying Lebanese families with severe (clinically homozygous) FH, aiming to identify this genetic gap by investigating more the combinatorial effect of different mutations that are known to cause the disease. Fasting venous blood samples were obtained, DNA was extracted, and Candidate Genes Analyses were conducted by Sanger sequencing following PCR amplifications of the coding exons of different genes.Through screening Lebanese families, we detected for the first time patients heterozygous for the Lebanese allele yet having normal cholesterol levels. In addition, some of the severely-affected patients, with no detected mutations in LDLR, have shown a rare mutation in the LDLRAP1 in an autosomal recessive mode of inheritance. This is a novel mutation to be reported only in a Lebanese cohort segregating with a wide spectrum of phenotype. Furthermore, we were able to report novel genotypes (combined ARH and ADH, and triple heterozygotes) among FH patients.These novel observations indicate that the LDLR mutation, especially the Lebanese allele, might not have a high prevalence in Lebanon as currently believed, and it might also be prevalent in normo-cholesterolemic patients. LDLRAP1 mutation gives the closure