Genetic Etiology Of Hedgehog Signaling Pathway And Scoliosis

BackgroundScoliosis is a spinal deformity characterized by a coronary curvature more than 10 degrees with or without vertebral malformation.More than a half of scoliotic patients are accompanied by other deformities which make it difficult in clinical diagnosis and treatment.The study of syndromes associated with scoliosis is an important means of understanding and recognizing the pathogenesis of spinal deformity.Though previous studies have suggested that the Hedgehog pathway may be associated with spinal deformities and other deformities associated with spinal deformities,there are still many questions:1.Because of the lack of large-scale scoliosis cohort studies,the correlation between spinal deformities and other deformities is not clear;2,Very few study gave a very specific and professional description about the spinal deformity that associated with Hedgehog pathway pathogenicity;3,As either congenital scoliosis or idiopathic scoliosis has been reported with the Hedgehog pathway-related genes,the relationship between CS and IS needs further study.Therefore,we will attempt to further explore and study the role of the Hedgehog pathway gene in scoliosis through a genetic perspective.Objects and Methods1?Perform retrospective study through the large-scale congenital scoliosis cohort to explore the potential correlation between vertebral malformation and other deformities.2?Design a Hedgehog pathway-related gene-based capture chip to detect the Hedgehog pathway gene mutation in the congenital scoliosis population.Give a genotype-phenotype analysis if necessary.3?Use Sanger sequencing to was verified the contribution of AKAP2 gene mutations in large-scale Chinese idiopathic scoliosis patients based on previous study.Results1?Among 356 cases of congenital scoliosis patients,56.5%of patients with other systemic deformities.Spinal cord/neural tube defects are the most common defects,followed by heart deformities.Compared with solitary CS,the phenotype in CS with other deformities was more complicated with more involvement of the segments.2?More CS patients accompanied by or simply accompanied by patients with cardiac malformations have spinal deformity involving the lower thoracic segments than solitary CS patients.3?Next generation target sequencing among 285 cases of CS patients found 12 patients with highly pathogenic Hedgehog pathway-related gene mutation.4?With further bioinformatics analysis and previous literature reported,we identified that PTCH2 p.R525Q,p.I1028T;PTCHI p.V1094M and GLI3 p.P1093L,p.R863C missense mutations may be the disease-causing mutations in patients with congenital scoliosis and other deformities.There is similarity in the phenotype of vertebral malformation among these patients.5?125 patients with idiopathic scoliosis were subjected to the Sanger sequencing of AKAP2 gene.It was found that one patient carrying rs765223801 mutation might be the pathogenic gene.The patient in addition to scoliosis is also accompanied by ventricular septal defect.Conclusion1?Spinal deformity is often associated with other system deformities,and a potential correlation between these deformities may exists.2?Hedgehog pathway-related gene mutations may play an important role in scoliosis(including CS and IS)and other multiple system malformations.