PDF(Pubmed)
Abstract：
BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing.
OBJECTIVE: The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants.
METHODS: Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members.
RESULTS: A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance.
CONCLUSIONS: This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.
OBJECTIVE: The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants.
METHODS: Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members.
RESULTS: A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance.
CONCLUSIONS: This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.
摘要：
背景：家族性高胆固醇血症（FH）是一种常见的遗传性代谢疾病，可导致过早的动脉粥样硬化，心血管疾病,甚至在年轻时死亡。已经鉴定的大约95%的引起FH的遗传变异存在于LDLR基因中。然而,全世界只有10%的FH人口得到了诊断和充分治疗，由于存在许多未知的变体，许多变异的致病性评分的不确定性，以及大量缺乏基因检测的个体。
目的：本研究的目的是鉴定LDLR基因中的一个新变异，该变异在一个中国家庭中引起FH，从而扩大了引起FH的变体的范围。
方法：患者来自北京安贞医院，首都医科大学。根据荷兰脂质临床网络（DLCN）标准进行FH诊断。进行全外显子组测序（WES）以鉴定先证者中引起FH的变体，和扩增子测序用于验证其家庭成员中的变体。
结果：招募了一个三代中国家庭，两名FH患者被临床诊断，两者都没有已知的FH引起变体。这两名FH患者和另一名可能的患者携带了一种新的变体，NC_000019.9（NM_000527.5）：c.89_92dup（NP_000518.1：p。Phe32Argfs*21),在导致移码的低密度脂蛋白（LDL）受体的配体结合域中。家庭中的FH成年人表现出严重的临床症状和他汀类药物治疗抵抗。
结论：这项研究发现了一种新的致病性LDLR变体，c.89_92dup，与严重FH临床表现和他汀类药物治疗耐药相关。
目的：本研究的目的是鉴定LDLR基因中的一个新变异，该变异在一个中国家庭中引起FH，从而扩大了引起FH的变体的范围。
方法：患者来自北京安贞医院，首都医科大学。根据荷兰脂质临床网络（DLCN）标准进行FH诊断。进行全外显子组测序（WES）以鉴定先证者中引起FH的变体，和扩增子测序用于验证其家庭成员中的变体。
结果：招募了一个三代中国家庭，两名FH患者被临床诊断，两者都没有已知的FH引起变体。这两名FH患者和另一名可能的患者携带了一种新的变体，NC_000019.9（NM_000527.5）：c.89_92dup（NP_000518.1：p。Phe32Argfs*21),在导致移码的低密度脂蛋白（LDL）受体的配体结合域中。家庭中的FH成年人表现出严重的临床症状和他汀类药物治疗抵抗。
结论：这项研究发现了一种新的致病性LDLR变体，c.89_92dup，与严重FH临床表现和他汀类药物治疗耐药相关。
