Rare missense variants in FNDC1 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. FNDC1 function was investigated in fndc1 null mutant zebrafish. Results: Rare variants were enriched in 84 genes, including RAF1 (Noonan syndrome), FBN1 (Marfan syndrome) and FNDC1, in individuals with severe AIS. FNDC1, 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). FNDC1 variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, FNDC1 rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the fndc1 locus in zebrafish resulted in increased bone mineral density. Conclusion: We broadened the phenotype associated with RAF1 and FBN1 variants and identified FNDC1 as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of FNDC1 missense variants with AIS.