Genetic Characteristics And Pathogenic Mechanism Of A Large Cohort Of SAPHO Syndrome Patients

BackgroundSAPHO syndrome is a rare disease with skin and bone lesions.Its clinical manifestations include acne,pustulosis,synovitis,osteitis and hyperostosis.Patients can be diagnosed with clinical manifestations,laboratory examination,characteristic bone scanning and spinal MRI.We have a deeper understanding of the pathogenesis and treatment of SAPHO syndrome with the development of orthopedics,traditional Chinese medicine,dermatology and rheumatology.It is reported that there are many factors may contribute to the development of SAPHO syndrome,including genetic susceptibility,infection of Propionibacterium acnes,immune system disorders,etc.The single nucleotide polymorphism or copy number variation of PSTPIP2,NOD2 and LPIN2 is related to the SAPHO syndrome.However,there are some defects in the study of genetic background in SAPHO syndrome,such as a relative small cohort size,insufficient genetic evidence and functional experiment verification.Objects1.To establish a large cohort of genome in SAPHO syndrome by whole exon sequencing;2.To propose the possible pathogenic genes and pathways screened by burden analysis and cluster analysis;3.To analyze the possible pathogenic mechanism of candidate gene and propose the pathogenic model of SAPHO syndrome;4.To analyze the clinical characteristics of the patients with pathogenic genes.Methods1.Establish the SAPHO syndrome patient cohort according to the inclusion criteria and exclusion criteria and collect the clinical data and peripheral blood samples of patients;2.Extract the DNA from peripheral blood samples and conduct whole exon sequencing and annotation;3.Establish the cohort of SAPHO patients and healthy control,conduct burden analysis and cluster analysis to find the pathogenic genes and pathways;4.Conduct Sanger sequencing,and analysis the possible pathogenicity mechanism of the pathogenic gene;5.Summarize the clinical phenotypes of patients and analyze the clinical characteristics of patients with pathogenic genes.Results1.A large cohort of SAPHO syndrome patients was established,and 236 patients were tested by burden test,and more than 600 candidate pathogenic genes were screened out.Cluster analysis was used to screen out the possible pathogenic pathway:antigen presenting pathway by MHC-?.2.Sanger test was conducted on 10 mutated genes in antigen presenting pathway by MHC-II,and the possible pathogenic mechanism of mutation in this pathway was proposed according to gene function.3.The clinical data of patients with genetic mutation in antigen presenting pathway by MHC-II were analyzed.It was found that the age of onset in this group was lower than that in the control group,but there was no significant difference in clinical symptoms and laboratory tests between the two groups.Conclusions1.Antigen presenting pathway by MHC-II is a possible pathogenic pathway of SAPHO syndrome;2.CLEC4A,CTSF,KLC2,LGMN,MAP1LC3B,MAPK9,OLR1,OSBPL1A,PIP5K1B,PRKCZ are important pathogenic genes;3.Patients with mutations in antigen presenting pathway by MHC-?have lower age of onset.