Genetic Research Of SAPHO Syndrome Based On Families

Background Synovitis,acne,pustulosis,hyperostosis and osteitis(SAPHO)syndrome is a rare disease which has dermal and osteoarticular lesions.Because the multifocal damage of bone and joint,it is difficult to differentiate SAPHO syndrome from bone metastasis.Many patients suffer from unnecessary surgeries and this brings patients great pain and burden.Furthermore,some patients with SAPHO syndrome developed a depressive disorder.However,the etiology of SAPHO syndrome is still unknown and doctors desire a guideline of treatment.So,it's very important to conduct this genetic research.Nowadays,few disease-causing genes of SAPHO syndrome have been found.Most of the studies reported are the analysis single nucleotide polymorphism(SNP)based on limited samples and without a functional experiment.Next generation sequencing has a high sensibility in finding common and rare variants and a great advantage over SNP association.This study is aimed to find the candidate genes of SAPHO syndrome by whole exome sequencing(WES)and copy number variant(CNV)analysis.Bisphosphonates can reduce the secretion of pro-inflammatory cytokines and inhibit the resorption of bone.Patients with SAPHO syndrome response to bisphosphonates effectively.What's more,only bisphosphonates are reported to cure the osteoarticular damage of SAPHO syndrome.In this study,we designed a prospective clinical trial to systematically investigate the efficacy of intravenous bisphosphonates in a cohort with SAPHO syndrome.Objects1.To build a genetic etiological study cohort of SAPHO syndrome in Chinese population.2.To investigate the candidate genes based on the WES and CNV analysis of SAPHO syndrome families.3.To validate the function of candidate variates and explore potential pathogenic mechanism.4.To investigate the efficacy of intravenous bisphosphonates and validate the pathogenic mechanism of SAPHO syndrome.Methods Based on the previous work,we increased our corhort size and collected clinical data and peripheral blood samples of SAPHO syndrome patients who came to PUMC Hospital.We extracted whole genome DNA of all participants in 18 families.By WES and CNV analysis,we investigate the candidate genes for SAPHO syndrome.Further,Sanger sequencing was used to study the variants of candidate genes in sporadic patients.Western blotting was used to investigate the influence on protein expression.Finally,we will propose a pathogenic mechanism and validate it by a prospective clinical trial of bisphosphonates.Results1.By the WES and CNV analysis,we find 4 candidate genes of SAPHO syndrome and propose that the aberrant level of active T cell causes the SAPHO syndrome and the inflammation may play an important role in this disease.2.We validate the disease-causing contribution of SIVAI c.5C>G.3.Bisphosphonates can relieve the spinal bone marrow edema by a long-term effect on inflammation.We suggest that bisphosphonates could be used as the first-line therapeutic drug for SAPHO syndrome,especially in patients with spinal BME.Conclusions1.By the WES and CNV analysis of 18 families,we found 4 candidate genes of SAPHO syndrome.2.Mutation SIVA1 c.5C>G could cause the SAPHO syndrome by regulating the necrosis of active T cells and the inflammatory level.3.Bisphosphonates can relieve the spinal bone marrow edema by an effect on inflammation.