Rare coding variants in axonemal dynein heavy chain genes are associated with adolescent idiopathic scoliosis

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common pediatric musculoskeletal disorder worldwide, characterized by atypical spine curvatures in otherwise healthy children. Human genetic studies have identified candidate genes associated with AIS, however, only a few of these genes have been shown to recapitulate adult-viable scoliosis in animal models. To further define susceptibility loci for AIS, we performed whole exome sequencing on a cohort of 195 Han Chinese AIS patients and 229 healthy controls. We identified members of the axonemal dynein family associated with both sporadic and familial AIS. We demonstrate that disruption of the dynein axonemal heavy chain 10 (dnah10) gene results in recessive adult-viable scoliosis in zebrafish. These dnah10 mutant zebrafish display reduced ependymal cilia beating and a disassembly of the Reissner fiber in the hindbrain and spinal canal, concurrent with the onset of body curvatures. Altogther, these results demonstrate that mutations in axonemal dynein genes are linked with human AIS and suggest that ependymal cell cilia function plays an essential role in maintaining spine alignment in humans.