Study On The Genetic Etiology Of Connective Tissue-related Genes And Congenital Scoliosis

Background:Congenital Scoliosis(CS)is one of the main causes of disability in adolescents,and it imposes a serious burden on patients' families and society.CS can be a complication in many hereditary connective tissue diseases(HCTD)such as Marfan syndrome,Ehlers-Danlos syndrome,osteogenesis imperfecta.There have been some related studies showing that connective tissue related genes have a certain correlation with the pathogenesis of scoliosis.Therefore,HCTD-related genes may also play a crucial role in the pathogenesis of CS.Purposes:1.Establish a CS patient cohort and identify HCTD-related genes;2.After whole exome sequencing,screen the candidate pathogenic genes with mutational burden test;3.Initially verify the pathogenicity of the candidate genes and analyze their possible pathogenic mechanisms;4.Analyze the contribution of candidate gene variants to phenotypes by arranging the phenotypes of CS patients.Methods:1.Continue to establish and expand CS patients and control cohorts based on previous study groups by establishing admission and exclusion criteria;2.Identify HCTD-related genes by means of Gene Ontology;3.Perform gene detection analysis on patients and controls by whole exome sequencing to screen for highly pathogenic mutations;4.Analyze the contribution of HCTD-related genes to CS by mutational burden test.Identification of candidate genes by subgroup analysis;5.Assessment of the pathogenicity of candidate genes by literature review and database analysis.6.Genotype-phenotype association studies of candidate genes were performed by arranging the phenotype of CS patients.Results:1.Identify 160 extracellular matrix structural constituents genes.2.In 647 CS patients and 828 controls,the polygenic mutational burden test failed to show significant differences.However,through subgroup analysis,two candidate pathogenic genes,COL3A1 and COL12A1,were finally identified.3.Four high-pathogenic novel mutations from COL3A1 and COL12A were identified,which may be new pathogenicity loci for CS.4.Through the genotype-phenotype association study,there is a more severe scoliosis Cobb angle for the mutation group carrying the highly pathogenic mutations of COL3A1 and COL12A.Conclusions:1.Connective tissue related genes have a certain contribution to the pathogenesis of CS;2.COL3A1 and COL12A1 may be important pathogenic candidate genes for CS;3.CS patients with COL3A1 and COL12A1 variants may exhibit more severe scoliosis Cobb angles.