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

CeMIA SA, Makriyianni 31, GR-41334 Larissa, Greece
Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Panepistimiou 3, GR-41500 Biopolis, Larissa, Greece
Hungarian Angioedema Center, 3rd Department of Internal Medicine, Semmelweis University, Kutvolgyi ut 4, H-1125 Budapest, Hungary
Department of Translational Medicine, University of Naples, Via S. Pansini 5, 80131 Naples, Italy
Reference Unit for Angioedema in Andalusia, Allergy Department, Virgen del Rocío University Hospital, Av Manuel Siurot s/n, 41013 Seville, Spain
Department of Allergology, Navy Hospital, Deinokratous 70, GR-11521 Athens, Greece
Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Sniadeckich 10, 31-531 Krakow, Poland
Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy
Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy
Allergy Unit, 2nd Department of Dermatology and Venereology, National and Kapodistrian University of Athens, University Hospital “Attikon”, Rimini 1, GR-12462 Chaidari, Athens, Greece
Author to whom correspondence should be addressed.
G.L. and F.P. contributed equally to this work as first authors.
J. Clin. Med. 2020, 9(11), 3402;
Received: 23 September 2020 / Revised: 13 October 2020 / Accepted: 19 October 2020 / Published: 23 October 2020
(This article belongs to the Special Issue Management and Treatment in Angioedema)
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. View Full-Text
Keywords: next-generation sequencing; pedigree analysis; primary angioedema; primary angioedema with normal C1 inhibitor next-generation sequencing; pedigree analysis; primary angioedema; primary angioedema with normal C1 inhibitor
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MDPI and ACS Style

Loules, G.; Parsopoulou, F.; Zamanakou, M.; Csuka, D.; Bova, M.; González-Quevedo, T.; Psarros, F.; Porebski, G.; Speletas, M.; Firinu, D.; del Giacco, S.; Suffritti, C.; Makris, M.; Vatsiou, S.; Zanichelli, A.; Farkas, H.; Germenis, A.E. Deciphering the Genetics of Primary Angioedema with Normal Levels of C1 Inhibitor. J. Clin. Med. 2020, 9, 3402.

AMA Style

Loules G, Parsopoulou F, Zamanakou M, Csuka D, Bova M, González-Quevedo T, Psarros F, Porebski G, Speletas M, Firinu D, del Giacco S, Suffritti C, Makris M, Vatsiou S, Zanichelli A, Farkas H, Germenis AE. Deciphering the Genetics of Primary Angioedema with Normal Levels of C1 Inhibitor. Journal of Clinical Medicine. 2020; 9(11):3402.

Chicago/Turabian Style

Loules, Gedeon, Faidra Parsopoulou, Maria Zamanakou, Dorottya Csuka, Maria Bova, Teresa González-Quevedo, Fotis Psarros, Gregor Porebski, Matthaios Speletas, Davide Firinu, Stefano del Giacco, Chiara Suffritti, Michael Makris, Sofia Vatsiou, Andrea Zanichelli, Henriette Farkas, and Anastasios E. Germenis 2020. "Deciphering the Genetics of Primary Angioedema with Normal Levels of C1 Inhibitor" Journal of Clinical Medicine 9, no. 11: 3402.

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