Tada Hayato, Hori Mika, Nomura Akihiro, Hosomichi Kazuyoshi, Nohara Atsushi, Kawashiri Masa-Aki, Harada-Shiba Mariko
Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
J Clin Lipidol. 2020 May-Jun;14(3):346-351.e9. doi: 10.1016/j.jacl.2020.03.002. Epub 2020 Mar 24.
Little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH).
We aimed to catalog 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 on requests from institutes all over Japan during more than past 2 decades.
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 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 guideline, or 3) CADD score > 10.
We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. However, 6 missense mutations were classified as variants of unknown significance. 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.
We provided the largest catalog 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.
关于日本家族性高胆固醇血症（FH）中低密度脂蛋白受体的致病突变的数据很少。
我们旨在对日本两个主要的FH治疗中心（金泽大学和国家脑心血管中心研究所）的低密度脂蛋白受体基因致病突变进行编目，在过去20多年里，这两个中心应日本各地机构的要求集中进行FH的基因检测。
本研究纳入了472个家庭的796名FH受试者，这些受试者的低密度脂蛋白受体基因存在非同义突变。通过桑格测序分析基因突变，并通过多重连接探针依赖扩增技术分析大片段重排。致病突变定义为：1）蛋白质截短变体；2）在ClinVar或人类基因突变数据库（HGMD）中注册为致病突变，或符合美国医学遗传学与基因组学学会指南的标准；3）CADD评分>10。
我们发现了138种不同的突变。其中，132种突变被认为是致病的，包括19种大片段重排突变。然而，6种错义突变被归类为意义未明的变异。由于奠基者基因效应，单一突变在金泽大学招募的FH受试者中占比高达41%，而在位于大阪的国家脑心血管中心研究所发现了许多单例突变。
我们提供了日本FH中最大的低密度脂蛋白受体基因致病突变编目。这不仅有助于确定日本人群，也有助于确定其他种族中低密度脂蛋白受体基因突变的致病性。
