Abstract
Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the low density lipoprotein receptor (LDLR), its ligand apoB (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Yet DNA sequencing does not identify mutations in these genes in a significant number of cases, suggesting that ADH has multiple genetic etiologies.
Through a combination of clinical examination, biochemical analysis, candidate gene approach and next-generation exome sequencing we investigated the genetic basis of an ADH phenotype in a proband of an Italian origin.
The proband presented with an acute myocardial infarction at age 43. He had tendinous xanthomas, xanthelasmas and elevated levels of total and LDL cholesterol, at 11.2 and 9.69 mmol/L, respectively, with normal levels of HDL cholesterol and triglycerides at 1.62 and 1.13 mmol/L, respectively. HPLC lipoprotein profile showed selective increase in LDL-C. DNA sequencing did not identify any mutation in the LDLR, PCSK9, LDLRAP1 and APOB gene. We then performed exome sequencing on three individuals from the family. The strongest evidence of association was found for the previously identified apolipoprotein E mutation (APOE, chromosome 19:45412053-55) known as APOE Leu167del, an in-frame three base-pair deletion. Computational biology confirmed the deleterious nature of this mutation. The Leu167del mutation is predicted to alter the protein structure of apoE near the α-helix within the receptor binding domain.
This report confirms a previous report that ADH can be caused by mutations within the APOE gene and represents the 4th loci causing ADH. Standard screening for ADH should include APOE gene.
•Candidate gene approach may fail to identify a significant number of ADH patients.•GWAS and next-generation exome sequencing has broadened the findings of contributing genes.•Standard screening for ADH should include APOE gene.•This may impact large registries of ADH and patients access to specialized medical care.