Hereditary angioedema (HAE) is a potentially life-threatening group of conditions that is often underdiagnosed or misdiagnosed. As HAE is typically diagnosed by detecting C1 inhibitor deficiency, there is a critical need for methods that can identify affected individuals with normal C1 inhibitor. The recent discovery of associations between PLG K330E and ANGPT1 A119S and HAE of unknown genetic cause (HAE-U), has raised the possibility that genetic evaluation could be used to diagnose HAE-U in patients with unexplained angioedema or non-confirmatory laboratory testing. We analyzed genome sequences from a generally healthy population cohort of 2820 adults and identified PLG K330E in one individual. Subsequent review of this participant’s medical history revealed symptoms clinically attributed to allergy of unknown etiology but that are consistent with published descriptions of HAE patients carrying the PLG K330E variant. The participant, a 31 year old female, reported lip and tongue angioedema, without wheals, which did not respond to treatment with steroids or antihistamines. The genotype-first approach demonstrated that detection of PLG K330E in undiagnosed or misdiagnosed individuals can identify patients actually affected with HAE-U. The genetic diagnosis will facilitate selection of appropriate treatment, discontinuation of therapies ineffective for this condition, and timely diagnosis of affected family members. The results support a role of PLG K330E in the pathogenesis of HAE and suggest that genetic testing be considered as an approach to diagnose patients with unexplained angioedema.

中文翻译：

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对一般健康人群队列的基因型优先分析支持基因检测用于诊断原因不明的遗传性血管性水肿

遗传性血管性水肿 (HAE) 是一组可能危及生命的疾病，通常被漏诊或误诊。由于 HAE 通常是通过检测 C1 抑制剂缺乏来诊断的，因此迫切需要能够识别具有正常 C1 抑制剂的受影响个体的方法。最近发现 PLG K330E 和 ANGPT1 A119S 与未知遗传原因的 HAE (HAE-U) 之间的关联，提高了遗传评估可用于诊断不明原因血管性水肿或非确认性实验室检测患者的 HAE-U 的可能性。我们分析了来自 2820 名成年人的总体健康人群的基因组序列，并在一个人中鉴定了 PLG K330E。随后对该参与者病史的回顾显示临床上归因于未知病因过敏的症状，但与已发表的携带 PLG K330E 变体的 HAE 患者的描述一致。参与者，一名 31 岁的女性，报告了唇和舌血管性水肿，没有风团，对类固醇或抗组胺药的治疗没有反应。基因型优先方法表明，在未诊断或误诊的个体中检测 PLG K330E 可以识别实际受 HAE-U 影响的患者。基因诊断将有助于选择合适的治疗方法，停止对这种情况无效的治疗，并及时诊断受影响的家庭成员。