Abstract 5: A Novel APOE p.Leu166del Mutation in Autosomal Dominant Familial Hypercholesterolemia

Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the low density lipoprotein receptor (LDLR), its ligand apoB (APOB) or in proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Yet DNA sequencing does not identify mutations in these genes in a significant number of cases with a phenotype of ADH, suggesting that ADH has multiple genetic etiologies. Through a combination of clinical examination, biochemical analysis, candidate gene sequencing, and next-generation exome sequencing, we identified an in-frame three base-pair deletion in apolipoprotein E (APOE, c.496_498delCTC) resulting in a novel Leu166del mutation. The proband presented with an acute myocardial infarction at age 43, requiring urgent coronary revascularization. He has extensive tendinous xanthomas and xanthelasmas, elevated levels of total cholesterol (11.2 mmol/L, 457 mg/dL)), LDL-C (9.69 mmol/L, 374 mg/dL), normal HDL-C (1.62 mmol/L, 63 mg/dL) and triglycerides levels (1.13 mmol/L, 100 mg/dL). A HPLC lipoprotein profile showed selective increase in LDL-C. One sister is heterozygous for the APOE Leu166del mutation and has an LDL-C of 5.3 mmol/L (180 mg/L). Another sister, with an LDL-C of 3.8 mmol/L (120 mg/dL) was not affected. DNA sequencing was performed for the LDLR, PCSK9, LDL-R adapter protein-1 (LDLRAP1) and exon 26 of the APOB genes no causal mutations were identified. We then performed exome sequencing on three individuals from the family. Approximately 54,000 variants were identified. We removed variants unlikely to be causal in the LDL-C genome-wide association studies, variants with a minor allele frequency >5%, synonymous or intronic variants and variants that did not fit a dominant model of transmission. We identified 49 missense mutations, 1 frameshift and 2 in-frame deletions in 52 genes. Using data derived from exome chip genotypes for association with LDL-C, the strongest evidence of association was found for the APOE gene. The Leu166del mutation is predicted to alter the protein structure of Apo E near the α-helix within the receptor binding domain. This report confirms that ADH can be caused by mutations within the APOE gene and represents the 4th loci causing ADH.

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