20.500.12556/RUL-156333 The CC2D2B is a novel genetic modifier of the clinical phenotype in patients with hereditary angioedema due to C1 inhibitor deficiency 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. hereditary angioedema C1 inhibitor deficiency genetic modifiers clinical phenotype genotype-phenotype correlation genetic variant SERPING1 CC2D2B hereditarni angioedem pomanjkanje zaviralca C1 geni modifikatorji klinični fenotip povezave genotip-fenotip genetska varianta SERPING1 CC2D2B true false true Angleški jezik Slovenski jezik Članek v reviji 2024-05-20 14:37:00 2024-05-20 14:37:02 2024-05-21 03:46:45 0000-00-00 00:00:00 2024 0 0 11 str. art. 148496 Vol. 919 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 66 1879-0038 10.1016/j.gene.2024.148496 194844163 1-s2.0-S0378111924003779-main.pdf 1-s2.0-S0378111924003779-main.pdf 1 4EA0461DF36C978925FF427ECE00A481 697a8f3991ba322dab4662309f1f647801d679574a5e959990d98171d1d4d483 e4ce2637-16a5-11ef-b600-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=183739 https://www.sciencedirect.com/science/article/pii/S0378111924003779 1 a7d1474d-16a5-11ef-b600-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=183738 Medicinska fakulteta Fakulteta za farmacijo Biotehniška fakulteta 0 0 0