Genetic Research Of Notch Signal Pathway And Congenital Scoliosis

BackgroundCongenital scoliosis (CS) is a rare congenital disease. It is defined as a lateral curvature of the spine exceeding 10 degrees due to congenital vertebral malformation during somitogenesis, which has a prevalence of 0.5 to 1/1000 live births. CS is the secondary major cause of scoliosis. Vertebral malformation in CS can be independent or accompanied with other systemic malformations, like central neural system, urogenital system, gastrointestinal system and cardiovascular system. CS is characterized as rapid-progression, severe and multiple deformities. It can cause severe physical and psychalogical problems, and lead to heavy burden to families and society. Because of unknown etiology, there is no effective test to predict CS in pregnance. And the treatment is only to slow down the progression without curing this disease. Therefore, research of etiology of CS can help control disease mobidity, and improve early diagnosis and early interference. Both genetic and environmental factors are important pathogenic etiology of CS. With more and more genetic researches about CS, some genes have been found which are associated with CS recently.Spine is developed from somits. Genes that regulate somitogenesis can cause vertebral malformation. Somitogenesis is controlled by gene oscillation in presomitic mesoderm, which is called segmentation clock. Notch, FGF and WNT signaling pathway are most important signal in somitogenesis, and Notch signaling pathway is the essential for segmentaion clock and segment border formation.Recently, null variants and a common hypomorphic allele of TBX6 has been found as a very important genetic etiology of CS, which can explain about 10% CS cases. TBX6 can regulate gene transcription in somitogenesis, such as DLL1, MESP2 and RIPPLY2. DLL1 is a gene in Notch signaling pathway. So Notch signaling pathway may be another important genetic etiology in CS.Objects1. To find out skeletal malformation associated genes in Notch signaling pathway.2. To validate pathogenesis of Notch signaling pathway in CS by Notch signaling pathway gene exon capture sequencing.3. To validate whether there are genes missing by capture sequencing and to further explore the genetic etiology of CS through Whole Exome Sequencing (WES).MethodsWe collected clinical data and peripheral blood samples of CS patients who came to PUMC Hospital Based on inclusion and exclusion criteria. We got the gene list of Notch signaling pathway in National Center for Biotechnology Information (NCBI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. And screened genes associated with skeletal malformation. We sequenced CS patients without TBX6 mutation by Notch signaling pathway gene exon capcure sequencing and selected family trios which is negative in capcure sequencing for WES.Results1.11 genes in Notch signaling pathway is associated with skeletal malformation, like Notch1, Notch2 and JAG1.2.8 pathogenic variants of Notch signaling pathway gene were found in 292 CS patients by capcure sequencing.3. No more pathogenic variants of Notch sinaling pathway genes were found in 4 family trios by WES. But a de novo MYH3 mutation was found in 1 family trio, which maybe the new gene for CS.Conclusions1. Notch signaling pathway is important in CS pathogenesis. Genes in Notch signaling pathway may be the causal gene of CS patients.2. The Notch signaling pathway gene exon capcure sequencing can find out the skeletal malformation associated genes in Notch signaling pathway. And WES can be a complementary test for capcure sequencing, which can discover new pathogenic genes for CS.3. MYH3 may be one causal gene for CS pathogenesis...