Abstract 198: Familial Hypercholesterolemia and Intra-Cranial Aneurysm: A Novel Phenotypic and Genetic Association

Abstract

Background: Autosomal dominant familial hypercholesterolemia (FH) is characterized by elevated levels of low density lipoprotein (LDL) cholesterol. Mutations in LDLR, APOB, and PCSK9 genes are established causes of this condition. However, in up to 20-40% of cases, the genetic cause has not been defined. FH is associated with coronary ectasias, but extra-cardiac vascular malformations have not been described. Methods: A subject with hypercholesterolemia was evaluated, and a three generation pedigree was constructed. Whole exome sequencing (WES) was performed (Illumina HiSeq 2500, 100x avg coverage) and reads were aligned to a human reference genome (hg19) using BWA. Variants were called with GATK Unified Genotyper and annotated using SeattleSeq. Results: Pedigree analysis suggested an autosomal dominant mode of inheritance of the hypercholesterolemia trait (Fig 1). Multiple family members also had intracranial aneurysms. Targeted analysis of the classical genes associated with FH (LDLR, APOB, and PCSK9) did not identify any missense, nonsense, or splice site variants with a minor allele frequency (MAF) < 0.01. Expanded analysis of the entire exome yielded rare missense variants (MAF < 0.001) in 845 genes and nonsense variants in 22 genes. Conclusions: Utilizing WES we rapidly screened an individual for pathogenic DNA variants in genes previously associated with FH. The genetic factor underlying our patient’s FH appears to be distinct from the known causes of FH. Genetic analysis of additional family members will be necessary to define the novel genetic cause of FH in this pedigree and explore the relationship of intracranial aneurysms with FH.