Abstract：
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.
摘要：
由C1抑制剂缺乏症（HAE-C1-INH）引起的遗传性血管性水肿是一种罕见的遗传性疾病，由SERPING1基因的致病性变异引起，其特征是肿胀和高度可变的临床表型。我们旨在确定易感临床症状的新型修饰遗传因素。我们对HAE-C1-INH的有症状和无症状（三个二组）家族成员进行了全外显子组测序（WES）和综合生物信息学分析。使用Sanger测序确定使用WES鉴定的选定变体(存在于所有无症状患者中,不存在于有症状患者中)。我们纳入了来自东南欧的88例临床特征良好的HAE-C1-INH患者（9例无症状），来自42个无关家庭。我们在23个基因中鉴定出39个变异体(ANKRD36C，ARGFX,CC2D2B,IL5RA,IRF2BP2,LGR6,MRPL45,MUC3A,NPIPA1,NRG1,OR5M1,OR5M3,OR5M10,OR8U3,PLCL1,PRSS3,PSKH2,PTPRA,RTP4,SEZ6,SLC25A5,VWA3A,和ZNF790）。我们选择了CC2D2B和PLCL1中的变体,其在HAE-C1-INH的整个组中使用Sanger测序进行分析。我们发现有症状和无症状患者之间CC2D2Bc.190A>G（rs17383738）变异的频率存在显着差异，其中杂合子在无症状HAE-C1-INH患者中比有症状患者更常见(55%vs23%;P=0.049,OR=4.24,95%CI1.07-14.69).我们的研究确定了改变HAE-C1-INH临床变异性的新遗传因素。我们进一步证明，在一大群人中，CC2D2B基因作为疾病修饰因子的重要性。基于连锁不平衡分析，CCNJ和ZNF518A基因也可能参与HAE-C1-INH的临床变异。
