Background

It is estimated that less than 10% of cases of familial hypercholesterolemia (FH) in the United States have been diagnosed. Low rates of diagnosis may in part be attributable to affected patients not meeting the clinical diagnostic criteria of the Dutch Lipid Clinic Network (DLCN), Simon Broome, or US MEDPED diagnostic criteria.

Objective

The objective of this study was to assess the utility of incorporating genetic testing into a patient's evaluation for FH.

Methods

We retrospectively reviewed patients seen in the Advanced Lipids Disorders Clinic at Johns Hopkins Hospital between January 2015 and May 2018. Between June 2018 and December 2018, patients were consented to a prospective registry. DLCN, Simon Broome, and MEDPED criteria were applied to each patient, before and after genetic testing. Genetic testing included sequencing and deletion duplication analysis of four genes (LDLR, PCSK9, APOB, and LDLRAP1).

Results

The retrospective review and prospective study identified 135 adult probands who were seen in our clinic for evaluation of heterozygous FH. Twenty-nine individuals (21%) were heterozygous for a pathogenic or likely pathogenic monogenic variant. Before genetic testing, using the DLCN criteria, 35 (26%) individuals met criteria for a definite diagnosis of FH. Thirty patients (22%) met criteria using Simon Broome, and 29 (21%) patients met criteria using US MEDPED before genetic analysis. Depending on the criteria, incorporating genetic testing identified 11–14 additional patients with FH.

Conclusions

Incorporating genetic testing diagnosed almost 50% more patients with definite FH in comparison to classification solely on clinical grounds.

中文翻译：

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结合基因检测显着增加了被诊断患有家族性高胆固醇血症的人数。

背景

据估计，美国只有不到 10% 的家族性高胆固醇血症 (FH) 病例被诊断出来。诊断率低可能部分归因于受影响的患者不符合荷兰脂质诊所网络 (DLCN)、Simon Broome 或美国 MEDPED 诊断标准的临床诊断标准。

客观的

本研究的目的是评估将基因检测纳入患者 FH 评估的效用。

方法

我们回顾性审查了 2015 年 1 月至 2018 年 5 月在约翰霍普金斯医院高级脂质疾病诊所就诊的患者。 2018 年 6 月至 2018 年 12 月期间，患者同意进行前瞻性登记。在基因检测之前和之后，DLCN、Simon Broome 和 MEDPED 标准适用于每位患者。基因检测包括四种基因（LDLR、PCSK9、APOB和LDLRAP1）的测序和缺失重复分析。

结果

回顾性审查和前瞻性研究确定了 135 名成人先证者，他们在我们的诊所就诊以评估杂合性 FH。29 个个体 (21%) 是致病性或可能致病性单基因变异的杂合子。在基因检测之前，使用 DLCN 标准，35 (26%) 个人符合 FH 的明确诊断标准。30 名患者 (22%) 符合使用 Simon Broome 的标准，29 名 (21%) 患者在遗传分析前使用 US MEDPED 符合标准。根据标准，结合基因检测确定了 11-14 名额外的 FH 患者。

结论

与仅根据临床原因进行分类相比，结合基因检测诊断出的确诊 FH 患者多出近 50%。