Abstract
Adolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder affecting ∼3% of children worldwide. Human genetic studies suggest a complex polygenic disease model for AIS with large genetic and phenotypic heterogeneity. However, the overall genetic etiology of AIS remains poorly understood. To identify additional AIS susceptibility loci, we performed whole-exome sequencing (WES) on a cohort of 195 Southern Chinese AIS patients. Bioinformatics analysis identified 237 novel rare variants associated with AIS, located in 232 new susceptibility loci. Enrichment analysis of these variants revealed 10 gene families associated with our AIS cohort. We screened these gene families by comparing our candidate gene list with IS candidate genes in the Human Phenotype Ontology (HPO) database and previous reported studies. Two candidate gene families, axonemal dynein and axonemal dynein assembly factors, were retained for their associations with ciliary architecture and function. The damaging effects of candidate variants in dynein genes dnali1, dnah1, dnaaf, and zmynd10, as well as in one fibrillin-related gene tns1, were functionally analyzed in zebrafish using targeted CRISPR/Cas9 screening. Knockout of two candidate genes, dnaaf1 or zmynd10, recapitulated scoliosis in viable adult zebrafish. Altogether, our results suggest that the disruption of one or more dynein-associated factors may correlate with AIS susceptibility in the Southern Chinese population.
Highlights
Adolescent idiopathic scoliosis (AIS) represented the majority of scoliotic disorders
Five clinical manifestations were measured to evaluate the states of AIS patients, including curve shape, left or right main curve, location of the apical vertebra, and number of tilted vertebrae
All the AIS patients are sporadic in origin and from ethnic Han Chinese residing in Southern China
Summary
Adolescent idiopathic scoliosis (AIS) represented the majority of scoliotic disorders. One of the hallmarks of AIS is the absence of obvious abnormalities of the vertebrae and without obvious neuromuscular dysfunction. Variants Zebrafish AIS evaluated based on the curve bending magnitude, which is usually referred to as the Cobb angle. A subset of AIS patients displaying more severe, progressive curves require costly surgical treatment, with long-term health implications (Cheng et al, 2015). In addition to the angle of spine curvature, additional variables including major curve direction, curve shape, location of the apical vertebrae, and curve length have been proposed in order to facilitate a more comprehensive classification of the sub-phenotypes of AIS (Lenke et al, 2003)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
