The CC2D2B is a novel genetic modifier of the clinical phenotype in patients with hereditary angioedema due to C1 inhibitor deficiency

Rupar, Nina (author), Šelb, Julij (author), Košnik, Mitja (author), Zidarn, Mihaela (author), Andrejević, Slađana (author), Čulav, Ljerka (author), Grivčeva-Panovska, Vesna (author), Korošec, Peter (author), Rijavec, Matija (author)

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic disorder caused by pathogenic variants in the SERPING1 gene and characterised by swelling and a highly variable clinical phenotype. We aimed to identify novel modifying genetic factors predisposing to the clinical symptoms. We performed whole exome sequencing (WES) and comprehensive bioinformatic analysis in symptomatic and asymptomatic (three duos) family members with HAE-C1-INH. Selected variants identified using WES (present in all asymptomatic and absent in symptomatic patients) were determined using Sanger sequencing. We included 88 clinically well-characterised HAE-C1-INH patients from south-eastern Europe (nine asymptomatic) from 42 unrelated families. We identified 39 variants in 23 genes (ANKRD36C, ARGFX, CC2D2B, IL5RA, IRF2BP2, LGR6, MRPL45, MUC3A, NPIPA1, NRG1, OR5M1, OR5M3, OR5M10, OR8U3, PLCL1, PRSS3, PSKH2, PTPRA, RTP4, SEZ6, SLC25A5, VWA3A, and ZNF790). We selected variants in CC2D2B and PLCL1, which were analysed using Sanger sequencing in the entire group of HAE-C1-INH. We found significant differences in the frequencies of the CC2D2B c.190A>G (rs17383738) variant between symptomatic and asymptomatic patients, where heterozygotes were more common in asymptomatic HAE-C1-INH patients in comparison to symptomatic patients (55 % vs 23%; P = 0.049, OR = 4.24, 95% CI 1.07-14.69). Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH. We further demonstrated, in a large cohort, the importance of the CC2D2B gene as a disease-modifying factor. Based on linkage disequilibrium analysis, the CCNJ and ZNF518A genes might also be involved in the clinical variability of HAE-C1-INH.

• Language: English
• Keywords: hereditary angioedema, C1 inhibitor deficiency, genetic modifiers, clinical phenotype, genotype-phenotype correlation, genetic variant, SERPING1, CC2D2B
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; FFA - Faculty of Pharmacy; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 11 str.
• Numbering: Vol. 919, art. 148496
• PID: 20.500.12556/RUL-156333
• UDC: 66
• ISSN on article: 1879-0038
• DOI: 10.1016/j.gene.2024.148496
• COBISS.SI-ID: 194844163
• Publication date in RUL: 20.05.2024

Record is a part of a journal

• Title: Gene
• Shortened title: Gene
• Publisher: Elsevier
• ISSN: 1879-0038
• COBISS.SI-ID: 23394309

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: hereditarni angioedem, pomanjkanje zaviralca C1, geni modifikatorji, klinični fenotip, povezave genotip-fenotip, genetska varianta, SERPING1, CC2D2B

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0360
• Name: Celostna obravnava alergijskih bolezni in astme v Sloveniji: od epidemiologije do genetike

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: J3-2532
• Name: Bradikininski angioedem: novi biološki označevalci in genetska predispozicija