Abstract: 【Abstract】 Objective 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.

Key words: Pemphigus, benign familial, Genetic association studies, Mutation, missense, Loss-of-function mutation, Age of onset, Meta-analysis, ATP2C1 gene