Background

Little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH).

Objective

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.

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 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.

Results

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.

Conclusions

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.

中文翻译：

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日本家族性高胆固醇血症LDL受体基因致病突变目录。

背景

日本家族性高胆固醇血症 (FH) 中 LDL 受体的致病突变数据很少。

客观的

我们旨在对日本 2 个主要 FH 护理中心（金泽大学和国立脑心血管中心研究所）中的 LDL 受体基因的致病突变进行编目，在此期间，已根据日本各地机构的要求集中进行了 FH 基因检测。超过过去 2 年。

方法

本研究包括来自 472 个家庭的 796 名具有 LDL 受体基因非同义突变的 FH 受试者。通过桑格测序以及针对大重排的多重连接探针依赖性扩增技术分析基因突变的突变。致病突变定义为 1) 蛋白质截短变异，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和基因组学学院指南的标准，或 3) CADD 评分 > 10 .

结果

我们发现了 138 个不同的突变。其中，132个突变被认为是致病性的，包括19个大的重排突变。然而，6 个错义突变被归类为意义未知的变体。单突变占金泽大学招募的 FH 受试者的 41%，主要是由于创始人基因效应，而位于大阪的国家脑和心血管中心研究所发现了许多单突变。

结论

我们提供了日本 FH 中最大的 LDL 受体基因致病突变目录。这有助于确定 LDL 受体基因突变不仅在日本人中而且在其他种族中的致病性。