PDF(Pubmed)
Abstract：
BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) carries a grave prognosis but is often underdiagnosed and undertreated. Confirmation of molecular diagnosis helps in planning effective management and determining prognosis accurately. Aim of the study: To determine the spectrum of mutations in the LDLR gene in a cohort of children with a clinical diagnosis of HoFH.
METHODS: Genomic DNA was extracted from peripheral blood samples of 8 patients, who were children of either sex, aged under 16 years, and diagnosed clinically with HoFH using the Simon Broome criteria. The potential variants in the LDLR gene were analysed by Sanger sequencing.
RESULTS: Fifty variations were found in the 8 patients; 39 (78%) were single nucleotide variations while 8 (16%) and 3 (6%) were deletions and insertions, respectively. The pathogenic variants in the LDLR gene were detected in four patients; three showed duplication in exon 17 (c.2416dupG) creating an amino acid change at position 806 (p.Val806GlyfsTer11) while one had a missense variant in the exon 9 at position c.1285G>A resulting in a change in amino acid at position 429 (p.Val429Met). The variants were found in heterozygous state in the parents or siblings of probands who showed pathogenic variants.
CONCLUSIONS: The frequency of disease-causing variants in the LDLR gene in our patients with HoFH was 50%. Further studies to characterise mutations in genes for apolipoprotein B, proprotein convertase subtilisin/kexin type 9, or LDL adaptor protein are suggested in all children with a clinical diagnosis of HoFH.
METHODS: Genomic DNA was extracted from peripheral blood samples of 8 patients, who were children of either sex, aged under 16 years, and diagnosed clinically with HoFH using the Simon Broome criteria. The potential variants in the LDLR gene were analysed by Sanger sequencing.
RESULTS: Fifty variations were found in the 8 patients; 39 (78%) were single nucleotide variations while 8 (16%) and 3 (6%) were deletions and insertions, respectively. The pathogenic variants in the LDLR gene were detected in four patients; three showed duplication in exon 17 (c.2416dupG) creating an amino acid change at position 806 (p.Val806GlyfsTer11) while one had a missense variant in the exon 9 at position c.1285G>A resulting in a change in amino acid at position 429 (p.Val429Met). The variants were found in heterozygous state in the parents or siblings of probands who showed pathogenic variants.
CONCLUSIONS: The frequency of disease-causing variants in the LDLR gene in our patients with HoFH was 50%. Further studies to characterise mutations in genes for apolipoprotein B, proprotein convertase subtilisin/kexin type 9, or LDL adaptor protein are suggested in all children with a clinical diagnosis of HoFH.
摘要：
背景：纯合子家族性高胆固醇血症（HoFH）预后严重，但通常未被诊断和治疗不足。分子诊断的确认有助于计划有效的管理和准确地确定预后。研究目的：确定临床诊断为HoFH的儿童队列中LDLR基因的突变谱。
方法：从8例患者的外周血样本中提取基因组DNA，他们是两种性别的孩子，16岁以下,并使用SimonBroome标准在临床上诊断为HoFH。通过Sanger测序分析LDLR基因中的潜在变体。
结果：在8例患者中发现了50个变异；39（78％）是单核苷酸变异，而8（16％）和3（6％）是缺失和插入，分别。在四名患者中检测到LDLR基因中的致病性变体；三个在外显子17（c.2416dupG）中显示重复，在806位产生氨基酸变化（p。Val806GlyfsTer11），而一个人在外显子9的位置c.128G>A处具有错义变体，导致位置429的氨基酸发生变化（p。Val429Met）。在显示致病性变异的先证者的父母或兄弟姐妹中发现了杂合状态的变异。
结论：我们的HoFH患者中LDLR基因致病变异的频率为50%。进一步研究以表征载脂蛋白B基因突变，所有临床诊断为HoFH的儿童都建议使用前蛋白转化酶枯草杆菌蛋白酶/kexin9型或LDL衔接蛋白。
方法：从8例患者的外周血样本中提取基因组DNA，他们是两种性别的孩子，16岁以下,并使用SimonBroome标准在临床上诊断为HoFH。通过Sanger测序分析LDLR基因中的潜在变体。
结果：在8例患者中发现了50个变异；39（78％）是单核苷酸变异，而8（16％）和3（6％）是缺失和插入，分别。在四名患者中检测到LDLR基因中的致病性变体；三个在外显子17（c.2416dupG）中显示重复，在806位产生氨基酸变化（p。Val806GlyfsTer11），而一个人在外显子9的位置c.128G>A处具有错义变体，导致位置429的氨基酸发生变化（p。Val429Met）。在显示致病性变异的先证者的父母或兄弟姐妹中发现了杂合状态的变异。
结论：我们的HoFH患者中LDLR基因致病变异的频率为50%。进一步研究以表征载脂蛋白B基因突变，所有临床诊断为HoFH的儿童都建议使用前蛋白转化酶枯草杆菌蛋白酶/kexin9型或LDL衔接蛋白。
