摘要目的:扩充家族性良性慢性天疱疮（HHD）的突变图谱，并深入探讨临床表型与基因型之间的关系。方法:回顾性选取2018年1月至2023年10月于山东第一医科大学附属皮肤病医院皮肤科门诊收治的HHD患者，分析他们的临床资料和血样。采用Sanger测序和全外显子组测序对34例HHD病例进行基因测序和突变分析。将ATP2C1基因的突变类型分为功能丧失突变（包括移码突变、终止突变和剪接突变）以及错义突变，对临床表型与基因突变类型之间的关系采用Fisher精确检验或独立样本 t检验进行分析，并采用Meta分析进一步检验。 结果:34例HHD患者均为中国汉族，男20例，女14例，年龄范围35 ~ 77岁。34例均成功检测到ATP2C1基因的致病突变，包括29种独立的突变，其中9种移码突变、8种剪接突变、6种错义突变和6种终止突变。HHD患者发病年龄在两类不同突变类型患者间存在显著差异，功能丧失突变组[（37.62 ± 10.10）岁]患者的发病年龄显著早于错义突变组[（49.63 ± 14.90）岁]，差异有统计学意义（ t = 2.62， P = 0.013）。然而，不同突变类型患者的性别、家族史、发病季节性、疾病严重程度或进展之间差异无统计学意义（均 P > 0.05）。Meta分析显示，在中国汉族HHD患者中携带功能丧失突变的HHD患者发病年龄显著早于携带错义突变的患者（均数差为-4.61岁，95% CI为-8.68 ~ -0.53； P = 0.030）。 结论:中国汉族HHD患者ATP2C1基因中携带功能丧失突变者的发病年龄显著早于携带错义突变者。

abstractsObjective:To expand the mutation spectrum of familial benign chronic pemphigus (HHD), and to deeply explore the relationship between clinical phenotypes and genotypes.Methods:HHD patients were retrospectively collected from the Department of Dermatology, Hospital for Skin Diseases, Shandong First Medical University from January 2018 to October 2023, and their clinical data and blood samples were also collected. Sanger sequencing and Whole-exome sequencing were performed on 34 HHD patients. Mutations in the ATP2C1 gene were classified into loss-of-function mutations (including frameshift mutations, nonsense mutations, and splicing mutations) and missense mutations. The relationship between clinical phenotypes and genetic mutation types was analyzed using Fisher's exact test or two-independent-sample t test, and further verified by meta-analysis. Results:The 34 HHD patients were all of Chinese Han nationality, including 20 males and 14 females, and their ages ranged from 35 to 77 years. Pathogenic mutations in the ATP2C1 gene were successfully identified in all the 34 patients, including 29 independent mutations, among which there were 9 frameshift mutations, 8 splicing mutations, 6 missense mutations, and 6 nonsense mutations. The age at onset was significantly earlier in the loss-of-function mutation group (37.62 ± 10.10 years) than in the missense mutation group (49.63 ± 14.90 years; t = 2.62, P = 0.013). However, there were no significant differences in gender, family history, disease seasonality, disease severity, or disease progression among patients with different mutation types (all P > 0.05). Meta-analysis showed that the age at onset was significantly earlier in Chinese Han patients with HHD carrying loss-of-function mutations than in those carrying missense mutations (mean difference: -4.61 years, 95% CI: -8.68 - -0.53 years, P = 0.030) . Conclusion:Chinese Han patients with HHD carrying loss-of-function mutations in the ATP2C1 gene showed significantly earlier ages at onset compared with those carrying missense mutations.