PO134 | FAMILIAL HYPERCHOLESTEROLEMIA 57-GENE PANEL MUTATIONAL ANALYSIS: INSIGHT INTO CARDIOVASCULAR RISK GENETIC PREDISPOSITION

A. Kura¹, E. Sticchi¹, G. Barbieri¹, F. Basso¹, P. Cantini¹, S. Suraci¹, M. Berteotti¹, E. Lotti¹, F. Crudele¹, G.M. Scaturro², A. Rogolino¹, A.M. Gori¹, R. Marcucci¹, B. Giusti¹ | ¹Atherothrombotic Diseases Center, Department of Experimental and Clinical Medicine, University of Florence - Careggi Hospital, Firenze, Italy; ²Meyer Children's Hospital IRCCS, Metabolic and Neuromuscular Unit, Firenze, Italy

Methods. We analyzed 191 patients with possible/probable/definite FH according to Dutch Lipid Clinic Network (DLCN) score. A targeted 57 genes (lipid metabolism, dyslipidaemias, polygenic FH) panel was evaluated through Illumina technology, using MiSeq platform. Variants identified were classified according to American College of Medical Genetics (Richards S et al.,2015) criteria. Continuous variables were expressed as median (interquartile range).
Results. We identified 80 rare variants in LDLR gene across 76 subjects. Sixty-eight of them had likely pathogenic (LP)/pathogenic (P) variants and we considered them as LDLR-positive (LDLR+). The remaining 123 patients were LDLR-negative (LDLR-), including 115 with no LDLR variants and 8 carrying LDLR benign (B)/likely benign (LB)/uncertain significance (VUS) variants. When patient clinical characteristics were considered across the two groups, LDLR+ subjects showed significantly higher LDL-C levels and a higher DLCN score [LDL-C: 233.0 (208.3-285.0) vs 220.0 (199.0-247.5) mg/dL, p=0.001; DLCN: 6 (4-7) vs 4 (4-5); p=0.000003], compared with LDLR- subjects. A trend towards higher levels of total cholesterol (TC) and higher CHD incidence was observed in LDLR+ [TC: 312.0 (281.5-360.5) vs 300.0 (267.0-331.0) mg/dL; p=0.07; CHD: 19.1% vs 9.8 %, p=0.08]. Higher Talmud score values in LDLR- with respect to LDLR+ [1.02 (0.90-1.11) vs 0.98 (0.86-1.06), p=0.08] were also found. Among LDLR+ patients, only 5 had variants exclusively in LDLR while 63 patients harboured at least one rare variant in other genes of the panel, of whom 17 had B/LB/VUS variants in APOB and LDLRAP1. Among LDLR- patients, a high proportion carried multiple rare variants: 67.5% had at least two and 36.6% had three or more rare variants across the 56-gene panel. Specifically, 39 rare variants were found in APOB, 3 in PCSK9 and 6 in LDLRAP1, alongside 297 in 45 of the remaining 53 panel genes. Patients with rare variants in both LDLR and other genes exhibited a trend of higher LDL-C levels compared to those with variants solely in LDLR [236.0 (220.0-288.0) vs 206.0 (195.5-254.0) mg/dL; p=0.17]. In particular, focusing on genes mainly associated to monogenic and polygenic FH (APOB, PCSK9, LDLRAP1, APOE, ABCG5, ABCG8, CELSR2, HFE, MYLIP, SLC22A1, NYNRIN, ST3GAL4), LDLR+ patients with at least two other variants in the selected panel exhibited significantly higher levels of TC and LDL-C compared to other LDLR+ [TC: 354.5 (312.0-400.3) vs 300.0 (276.3-336.3) mg/dL, p=0.02; LDL-C: 275.5 (246.3-314.8) vs 227.5 (203.3-265.3) mg/dL, p=0.01] and a trend toward higher DLCN score [6.5 (5.8-9.0) vs 6.0 (4.0-7.0), p=0.07].
Conclusions. These findings highlight the complexity of FH genetics, suggesting the possible contribution of rare or common genetic variants burden in modulation of clinical phenotype not only in polygenic hypercholesterolemia but also in LDLR+ monogenic FH.