The Association Of Clinical And Genetic Factors With Surgical Prognostic Outcomes And The Pathogenicity Of Chondrogenesis-related Variants In A Skeletal Deformity Cohort

Background:In recent years,with the rapid development of Next Generation Sequencing(NGS)technology,the exploration of the genetic etiology of various skeletal deformity diseases has become more and more in-depth.However,the current research still focuses on the exploration of etiology and pathogenesis.For spinal deformity,a common clinical skeletal deformity disease,the research on etiology and pathogenesis is still not enough to make up for the shortcomings of clinical treatment.Especially for complex spinal three-dimensional deformities such as congenital scoliosis(CS)and idiopathic scoliosis(IS),there is still a lack of effective closed-loop from clarifying genetic etiology,establishing risk detection methods,evaluating clinical prognosis risk to guiding accurate treatment of diseases.Therefore,based on the existing clinical phenotype,genetic data and etiological research methods,exploring the potential association between genotype-phenotype and treatment and prognosis is of great significance for understanding the disease,carrying out accurate treatment,providing risk assessment methods and reducing the social burden of the disease.Objects:Based on the large-scale scoliosis cohort of the DISCO research group(Deciphering Disorders Involving Scoliosis and Comorbidities,http://www.discostudy.org/),we retrospectively analyzed risk factors for postoperative perioperative complications in IS patients who underwent spinal correction surgery.Our aim was to stratify patients for clinical risk and predict the occurrence of perioperative adverse events.We comprehensively analyzed the contribution of Mendelian genetic etiologies in the CS cohort,explored the association between genetic etiologies and CS prognosis,and constructed a genetic risk prediction model based on molecular diagnostic classification.We compared the clinical characteristics of patients with chondrogenesis defect-related gene mutations and patients without chondrogenesis defect-related gene mutations by genotype-phenotype association analysis,with the aim of exploring potential associations between phenotype and genotype,which will assist in the identification of high-risk patients.At the same time,we analyzed the pathogenicity of the candidate gene COMP for skeletal deformities.Method:The clinical and imaging data of 146 IS patients in the DISCO cohort were collected and retrospectively analyzed.Univariate analysis and multivariate logistic regression analysis were performed on the risk factors of perioperative complications in patients to study the influence of clinical characteristics and treatment methods on clinical prognosis.Based on CS patients from DISCO research group,through whole-exome sequencing(WES)and data annotation and analysis of 303 CS patients,the pathogenic variants were evaluated and screened and Sanger validation was performed.According to the biological process involved in the pathogenic gene,the correlation between molecular diagnostic classification and clinical prognosis was further studied.The genotype-phenotype association analysis was used to study the relationship between chondrogenesis defect-related gene mutations and the clinical manifestations of CS.At the same time,we analyzed the pathogenicity of the candidate gene COMP for skeletal deformities.Result:Among the 146 IS patients,21(14.4%)had perioperative complications.Multivariate analysis found that independent risk factors for perioperative complications included changes in Cobb angle(OR=1.085,95%CI=1.035-1.137,P=0.001)and spinal osteotomy(OR=3.565,95%CI=1.039-12.236,P=0.043).Among the 303 CS patients included,after WES and data analysis and interpretation,a total of 53(17.5%)patients were found to have a definite molecular diagnosis.By querying the public data of the National Center for Biotechnology Information(NCBI)and the Gene Ontology(GO)database,we identified the biological process to which the disease-causing genes belong.The causative genes were categorized as:1)connective tissue disorder;2)chondrogenesis defect;3)myogenesis defect;4)TBX6associated congenital scoliosis(TACS);and 5)others.Multivariate association analysis found that the patients with chondrogenesis-related gene defects(OR=7.73,95%CI=1.64-42.90,P=0.011),accompanied by thoracic/rib deformities(OR=2.81,95%CI=1.19-6.62,P=0.011),and the American Society of Anesthesiologists(ASA)grade≥3(OR=14.22,95%CI=1.18-337.4,P=0.042)were more likely to develop perioperative and postoperative complications.By summarizing the clinical characteristics of 8 CS patients with chondrogenesisrelated gene mutations in the CS cohort included in this study,a genotype-phenotype association analysis showed that the preoperative maximum Cobb angle was larger in patients with chondrogenesis-related gene mutations.From the included families,a novel heterozygous missense mutation in COMP(c.1153G>T,p.Asp385Tyr)was identified,and the mutation caused the typical cosegregation of clinical phenotype in the multiple epiphyseal dysplasia(MED)family,and we found an unreported new clinical phenotype of flatfoot.Conclusion:Based on cohort study of 146 IS patients,a risk prediction model for postoperative adverse events was constructed,which provided a reference for preoperative risk factor stratification and treatment selection.Based on the cohort study of 303 CS patients,the gene mutation spectrum of the CS has been constructed.Through the integrated analysis of genetic and clinical data,we found that chondrogenesis-related gene mutations may be an important marker leading to poor patient prognosis.In the future,preoperative comprehensive phenotypic assessment and WES for CS patients will facilitate the implementation of precision diagnosis and treatment.We found that the c.1153G>T mutation of the COMP gene can lead to classic MED disease,and further discovered a new clinical phenotype-flatfoot,which expanded the disease mutation spectrum and phenotype spectrum of COMP causing AD-MED.