Abstract

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 LDLR or APOB, or gain-of-function mutations in PCSK9. 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.

摘要

家族性高胆固醇血症 (FH) 是一种单基因疾病，其特征是终生暴露于高 LDL-C 水平，可导致早发性冠心病 (CHD)。迄今为止确定的 FH 的主要原因包括LDLR或APOB中的功能丧失突变，或PCSK9中的功能获得性突变. FH 嫌疑人的早期诊断和基因检测对于改善受影响个体的预后至关重要，因为降脂治疗可有效预防 CHD 相关的发病率和死亡率。在本研究中，我们使用新一代测序 (NGS) 面板对代表 FH 家族或一般人群的两项冰岛研究中的 FH 罪魁祸首突变进行了全面筛查。我们确认了 FH 家族中所有先前已知的突变，并确定了两个在年轻时被临床误诊的受试者。我们在冰岛 FH 家族中发现了六个新突变，并在基于人群的一般研究中检测到了三个致病突变。NGS panel 的应用揭示了在识别致病突变方面的大量诊断结果，或 68。