Deciphering the Genetics of Primary Angioedema with Normal Levels of C1 Inhibitor

Abstract

The genetic alteration underlying the great majority of primary angioedema with normal C1 inhibitor (nl-C1-INH-HAE) cases remains unknown. To search for variants associated with nl-C1-INH-HAE, we genotyped 133 unrelated nl-C1-INH-HAE patients using a custom next-generation sequencing platform targeting 55 genes possibly involved in angioedema pathogenesis. Patients already diagnosed with F12 alterations as well as those with histaminergic acquired angioedema were excluded. A variant pathogenicity curation strategy was followed, including a comparison of the results with those of genotyping 169 patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE), and only filtered-in variants were studied further. Among the examined nl-C1-INH-HAE patients, carriers of neither the ANGPT1 p.Ala119Ser nor the KNG1 p.Met379Lys variant were found, whereas the PLG p.Lys330Glu was detected in four (3%) unrelated probands (one homozygote). In total, 182 different variants were curated, 21 of which represented novel mutations. Although the frequency of variants per gene was comparable between nl-C1-INH-HAE and C1-INH-HAE, variants of the KNG1 and XPNPEP1 genes were detected only in nl-C1-INH-HAE patients (six and three, respectively). Twenty-seven filtered variants in 23 different genes were detected in nl-C1-INH-HAE more than once, whereas 69/133 nl-C1-INH-HAE patients had compound heterozygotes of filtered variants located in the same or different genes. Pedigree analysis was performed where feasible. Our results indicate the role that alterations in some genes, like KNG1, may play in disease pathogenesis, the complex trait that is possibly underlying in some cases, and the existence of hitherto unrecognized disease endotypes.

Screening for Plasminogen Mutations in Hereditary Angioedema Patients

“…To date, only a few case series of patients with PLG-HAE have been reported [ 3 , 4 , 13 , 14 , 15 , 16 ] and this was the first family diagnosed with PLG-HAE in Hungary.…”

“…PLG-HAE is characterized by clinical manifestations that first occur usually during adulthood, most commonly involve the tongue and the face, and the acute episodes of AE may be triggered by ACEI therapy. The disorder follows an autosomal dominant trait; however, its penetrance is lower than that of C1-INH-HAE [ 3 , 4 , 13 , 14 , 15 , 16 ]. In HAE, genetic testing is becoming ever more important along with complement profiling.…”

“…: 9, max. : 94 years)) (previously, 53 unrelated U-HAE patients were screened for mutations in PLG and further genes [ 13 ] without overlap between the current and the previously published patient groups). Fifty-one of these 124 patients belonged to 16 families (DNA samples were unavailable from the family members of the remaining 73 subjects).…”

The Genetics of Hereditary Angioedema: A Review

“…Table 1 summarizes the mutations described in F12 and in the other genes associated with nC1-INH-HAE. In the following years families or individuals with nC1-INH-HAE, in particular families with nC1-INH-HAE and without mutation in the F12 gene, were analyzed often by whole-exome sequencing (WES), but also by a direct candidate gene approach [33][34][35][36][37][38][39]. These studies allowed the identification of five new genes linked nC1-INH-HAE.…”

Rediscovery of a forgotten disease: Hereditary Angioedema

“… 32 During the next years, the advent of high-throughput next-generation sequencing (NGS) technologies accelerated the coverage of the missing part of nC1-INH-HAE genetics, and nC1-INH-HAE was further fragmented by the discovery of 4 novel target genes ( ANGPT1 , PLG , KNG1 , and MYOF ) 33 , the list of which is expected to grow up during the forthcoming years. 34 The most important contribution of these discoveries was the broadening of our concept of HAE pathophysiology from an exclusive focus on the contact system to the inclusion of the vascular bed itself. 35 Elegant studies provide convincing evidence that HAE is a model of the so-named paroxysmal permeability disorders characterized by an impairment of the endothelial barrier function.…”