Whole-exome sequencing in patients with clinical diagnosis of Familial Hypercholesterolaemia

Abstract

Familial hypercholesterolemia (FH) results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, common caused by a loss-of-function mutation in the LDLR receptor gene (LDLR), by mutations in the gene enconding apolipoprotein B (APOB) or rare dominant gain-of-function mutations in a member of the proprotein convertase family (PCSK9). However, mutations which encodes a protein required for clathrin-mediated internalization of the LDLR (LDLRAP1) by the liver, has also been described as a recessive form of FH. The presence of mutations in other genes (CYP7A1, enzyme that catalyses the first step in the hepatic catabolism of cholesterol, and SREBP-2, a transcription factor that bind to the sterol regulatory element ) have been described, but these are very rare causes of hypercholesterolaemia. In the Portuguese FH Study only 40% of clinical FH patients have an identifiable mutation so, other mutations in these genes or other gene defects must exist to explain the cause of hypercholesterolemia in the remaining families. Next-generation high-throughput DNA sequencing techniques are opening fascinating opportunities in life sciences. The next-generation sequencing (NGS) technologies offer novel and rapid ways for genome-wide characterisation and profiling of mRNAs, small RNAs, transcription factor regions, structure of chromatin and DNA methylation patterns, microbiology and metagenomics.