ABSTRACT
BACKGROUND AND AIMS: Apolipoprotein B plays a crucial role in regulating plasma cholesterol by mediating the interaction of low-density lipoprotein (LDL) with LDL receptors in the liver. Inherited mutations in this gene may increase the risk of developing premature atherosclerotic cardiovascular disease, especially in individuals with familial hypercholesterolemia type 2 (FH2). The aim of this study is to identify APOB variants that may indicate pathogenicity in a sample of the Brazilian population using a data bank exome sequencing study by NGS in a Brazilian population phenotypically diagnosed by clinical and laboratory profile. This finding is going to improve genetic hypercholesteremia diagnosis. METHODS: High-quality DNA samples (n»300) were sequenced using an exon-targeted gene sequencing (ETGS) strategy to identify variants in FHrelated genes. Pathogenicity classification was based on criteria established by the American College of Medical Genetics and Genomics (ACMG), also using information from ClinVar and pathogenicity scores from previous association studies. RESULTS: A total of 121 variants were identified in APOB, of which four are novel variants missense (p.Thr626Asn, p.Ile2750Thr, p.Gln2078Lys and p.Met4184Arg). After curating pathogenicity scores, variants were classified according to the ACMG criteria. Among them four as pathogenic or likely pathogenic (p.Pro2739Leu, p.His1923Arg, p.Pro994Leu and p.Pro877Leu), and 21 variants had uncertain significance. Additionally, 92 previously known variants with uncertain significance were classified as benign or likely benign. The results were submitted to Clinvar for actualization of pathogenicity. CONCLUSIONS: These results improve the molecular diagnosis associating APOB variants with the clinical phenotype of hypercholesterolemia.