Background

Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain).

Objectives

This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria.

Methods

Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR.

Results

On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype.

Conclusions

These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.

中文翻译：

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大加那利岛：家族性高胆固醇血症的遗传分离物。

背景

在加那利群岛（西班牙）尚未普遍进行家族性高胆固醇血症（FH）的遗传诊断。

目标

这项研究旨在对大加那利岛的FH患者人群进行遗传学表征。

方法

根据荷兰血脂诊所网络的标准，研究对象为在大加那利岛一家三级医院就读的70例不相关的索引病例，临床诊断为FH。鉴于遗传学研究阳性的前10例中有7例是LDLR基因[p。（Tyr400_Phe402del）]中单个突变的携带者，因此开发了一种基于特异性聚合酶链反应的检测方法来检测该变体作为首次筛选踩到其余的科目。在没有这种突变的人群中，使用包括LDLR，APOB，PCSK9，LDLRAP1，APOE，STAP1和LIPA基因在内的下一代测序小组完成分子诊断，并将拷贝数变异检测纳入LDLR中。

结果

总体而言，有44位受试者（62％）进行了积极的遗传研究，其中30位（68％）是p。（Tyr400_Phe402del）变体的杂合子携带者。11名受试者在LDLR中携带其他突变，包括新突变NM_000527.4：c.877dupG; NP_000518.1：第（Asp293Glyfs * 8）。未分类的PCSK9基因变体在一个受试者中发现[（NM_174936.3：c.1496G> A; NP_777596.2：第（Arg499His）]。其它单患者中有突变APOB（杂合的）和在LIPA（纯合的）。所有鉴定出的变体与疾病表型共分离。

结论

这些发现暗示了大加那利岛p。（Tyr400_Phe402del）LDLR突变的奠基者效应。可以在该区域实施一种经济有效的FH遗传学诊断本地筛查策略。