Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. 
Despite a strong genetic basis, few genes have been associated with AIS and the 
pathogenesis remains poorly understood. In a genome-wide rare variant burden 
analysis using exome sequence data, we identified fibrillin-1 (FBN1) as the most 
significantly associated gene with AIS. Based on these results, FBN1 and a 
related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 
669 controls. In individuals of European ancestry, rare variants in FBN1 and 
FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house 
controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project 
controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6)). Scoliosis severity in AIS cases 
was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in 
an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants 
may be useful as predictors of curve progression. Clinical evaluations revealed 
that the majority of AIS cases with rare FBN1 variants do not meet diagnostic 
criteria for Marfan syndrome, though variants are associated with tall stature 
(P = 0.0035) and upregulation of the transforming growth factor beta pathway. 
Overall, these results expand our definition of fibrillin-related disorders to 
include AIS and open up new strategies for diagnosing and treating severe AIS.