*A Novel ABCG8 Variant and Apo(A) Short Isoform Associated with Premature Atherosclerosis and Familial Hypercholesterolemia Phenocopy.

Abstract

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis We report a patient with a rare ABCG8 mutation, that when combined with Apo(a) short isoforms may represent a familial hypercholesterolemia (FH) phenocopy. Objective/Purpose A 44-year-old African American male with prior myocardial infarction (MI) at the age 24 with subsequent coronary artery bypass graft who had rapid progression of atherosclerosis despite having a corrected LDL of zero. Methods Lp(a) was 127 mg/dL and LDL was 40 mg/dL and he had been on evolocumab and rosuvastatin. The corrected LDL accounts for the cholesterol contained in Lp(a) using the formula LDLcorr =LDL- 0.3x Lp(a) mass. Thus, his LDLcorr was zero. He underwent genetic testing with GBinsight which demonstrated he had Apo(a) short isoforms, which is associated with elevated Lp(a). He was also heterozygous for an extremely rare ABCG8 variant p.Gly212Glu (rs1318623110) which has not been previously reported. This variant is predicted to be deleterious and Gly212 is highly conserved across vertebrates. Mutations in ABCG5 or ABCG8 can be associated with increased LDL and risk for CAD. In addition, elevation of Lp(a) can be associated with 3 to 4 folds increased risk. This novel mutation, along with the elevated Lp(a) may help to explain his FH phenocopy presentation. Results We hypothesized that his premature disease progression may have been secondary to inflammation, atherogenesis or prothrombosis associated with Lp(a) with the added potentially deleterious effect of the ABCG8 mutation. His clinical course with his first MI at age 24 mimics that of FH, thus making him a phenocopy. We enrolled him in the randomized Lp(a)HORIZON trial evaluating the effect of pelacarsen in lowering Lp(a). However, he subsequently had an episode of unstable angina requiring additional intervention. Conclusions When assessing patients with suspected FH, mutations in genes other than LDLR, APOB, and PCSK9 should be evaluated. In this case, a mutation in ABCG8 gene along with Apo(a) short form isoforms may help explain the patient's disease progression and FH phenocopy presentation. In addition, ezetimibe may be beneficial in patients with ABCG5/8 mutation. His marked disease progression despite having a LDLcorr of zero highlights the importance of considering factors other than just LDL. Nothing to disclose.