Molecular screening of familial hypercholesterolemia in Icelanders

Familial hypercholesterolemia (FH) is a monogenic disease characterized by a lifelong exposure to high LDL-C levels that can lead to early onset coronary heart disease (CHD). The main causes of FH identified to date include loss-of-function mutations in <i>LDLR</i> or <i>APOB</i>, or gain-of-function mutations in <i>PCSK9</i>. Early diagnosis and genetic testing of FH suspects is critical for improved prognosis of affected individuals as lipid lowering treatments are effective in preventing CHD related morbidity and mortality. In the present study, we carried out a comprehensive screening, using a next-generation sequencing (NGS) panel, for FH culprit mutations in two Icelandic studies representative of either FH families or the general population. We confirmed all previously known mutations in the FH families, and identified two subjects that had been misdiagnosed clinically at young age. We identified six new mutations in the Icelandic FH families and detected three pathogenic mutations in the general population-based study. The application of the NGS panel revealed substantial diagnostic yields in identifying pathogenic mutations, or 68.2% of those with definite clinical diagnosis of FH in the family material and 5.6-fold enrichment in the population-based genetic testing.

家族性高胆固醇血症（Familial hypercholesterolemia, FH）是一类单基因遗传病，患者终身处于高水平低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）暴露状态，可引发早发性冠心病（coronary heart disease, CHD）。截至目前已明确的FH主要致病机制包括：低密度脂蛋白受体基因（LDLR）或载脂蛋白B基因（APOB）发生功能丧失突变，或前蛋白转化酶枯草溶菌素9基因（PCSK9）发生功能获得突变。早期对FH疑似患者开展诊断与基因检测，对改善患者预后具有关键意义——降脂治疗可有效预防冠心病相关的发病与死亡。本研究采用新一代测序（next-generation sequencing, NGS）靶向检测panel，针对两项分别代表FH家族队列与普通人群队列的冰岛研究，全面筛查FH致病突变。我们在FH家族队列中验证了所有既往已知的致病突变，并发现2名曾在青年时期被临床误诊的受试者；在冰岛FH家族队列中鉴定出6种全新突变，同时在普通人群队列中检出3种致病性突变。本次NGS靶向检测panel的应用展现出可观的诊断效能：在家族队列中，确诊为FH的受试者中68.2%可检出致病性突变；在人群队列中，基因检测的阳性检出率提升了5.6倍。