Familial hypercholesterolemia – Targeted whole gene sequencing as a diagnostic approach

IF 1.4 Q3 PERIPHERAL VASCULAR DISEASE

Atherosclerosis plus Pub Date : 2024-12-11 DOI:10.1016/j.athplu.2024.12.001

Emma Adolfsson , Nils Johan Fredriksson , Jon Jonasson , Anna Nordenskjöld , Anna Green

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Abstract

Background and aims

Familial hypercholesterolemia (FH) and other disorders with similar features are common genetic disorders that remain underdiagnosed and undertreated, due in part to the cost of screening. The aim of this study was to design and implement a whole gene targeted NGS panel for the molecular diagnosis of FH and statin intolerance with an emphasis on high quality variant calling, including copy number analysis.

Methods

A whole gene panel for hybridisation-based short read NGS was designed for the dominant FH-genes low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proproteinconvertas subtilisin/kexin type 9 (PCSK9), apolipoprotein E (APOE) and the recessive FH-genes low density lipoprotein receptor adaptor protein 1 (LDLRAP1), ATP binding cassette subfamily member 5/8 (ABCG5/8) and lipase A, lysosomal acid type (LIPA), as well as solute carrier organic anion transporter family member 1B1 (SLCO1B1), not an FH gene but linked to statin intolerance. Polygenetic risk score markers were also included. The panel was used for screening of a Swedish FH-study population (n = 133).

Results

The panel sequencing resulted in high coverage and confident variant calling of included genes. Known causal variants were found in common dominant FH-genes in 43 % of the cohort. Copy number variants were found in LDLR in 10 individuals and a whole gene deletion of SLCO1B1 in one individual. In addition, coding variants in recessive genes and rare non-coding intronic and untranslated region variants were found in a large proportion of the study individuals highlighting the need for extended gene panels.

Conclusions

This new tool can be used for a comprehensive high-quality molecular genetic analysis according to guidelines for the diagnosis and treatment of FH.

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家族性高胆固醇血症-靶向全基因测序作为诊断方法。

背景和目的：家族性高胆固醇血症（FH）和其他具有类似特征的疾病是常见的遗传性疾病，但由于筛查成本等原因，这些疾病的诊断率和治疗率仍然偏低。本研究的目的是设计并实施一个全基因靶向 NGS 面板，用于 FH 和他汀类药物不耐受的分子诊断，重点是高质量的变异调用，包括拷贝数分析：方法：针对显性 FH 基因低密度脂蛋白受体 (LDLR)、脂蛋白 B (APOB)、9 型丙roteinconvertas subtilisin/kexin (PCSK9)、脂蛋白 E (APOE) 和隐性 FH 基因低密度脂蛋白受体适配蛋白 1 (LDLRAP1)，设计了基于杂交的短读 NGS 全基因面板、ATP 结合盒亚族成员 5/8 (ABCG5/8) 和溶酶体酸型脂肪酶 A (LIPA)，以及溶质载体有机阴离子转运体家族成员 1B1 (SLCO1B1)，后者不是 FH 基因，但与他汀类药物不耐受有关。此外还包括多基因风险评分标记。该基因组用于筛查瑞典的 FH 研究人群（n = 133）：结果：该基因组测序结果覆盖率高，对所包含基因的变异调用有把握。在43%的研究人群中，常见的显性FH基因中发现了已知的因果变异。在10人的LDLR中发现了拷贝数变异，在1人的SLCO1B1中发现了全基因缺失。此外，在很大一部分研究个体中还发现了隐性基因的编码变异以及罕见的非编码内含子和非翻译区变异，这凸显了扩展基因面板的必要性：这种新工具可用于根据 FH 诊断和治疗指南进行全面、高质量的分子遗传分析。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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