Rare missense variants in are associated with severe adolescent idiopathic scoliosis.

BACKGROUND

Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.

METHODS

To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. function was investigated in null mutant zebrafish.

RESULTS

Rare variants were enriched in 84 genes, including (Noonan syndrome), (Marfan syndrome) and in individuals with severe AIS. , which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the locus in zebrafish resulted in increased bone mineral density.

CONCLUSION

We broadened the phenotype associated with and variants and identified as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of missense variants with AIS.