Abstract 207: A Catalogue of the Pathogenic Mutations of LDL Receptor Gene in Japanese Familial Hypercholesterolemia

Abstract

Background: Familial hypercholesterolemia (FH), mainly caused by LDL receptor gene mutation is attracting a lot of attention associated with the development of novel therapies. However, rare mutations tend to be ethnicity-specific, hence, it is always difficult to determine pathogenicity of LDL receptor gene mutation in a single individual in a certain ethnicity. Currently, little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH). Objective: We aimed to catalogue the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally upon requests from institutes all over Japan during more than past two decades. Methods: 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification (MLPA) technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in Clinvar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics (ACMG) guideline, or 3) CADD-score > 10. Results: We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. Whereas, 6 missense mutations were classified as variants of unknown significance (VUS). A single mutation accounted for as much as 41 % of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas, many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka. Conclusions: We provided the largest catalogue of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities.