Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis

Abstract

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.

Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis

“…In addition, we could not find any putative functional variants in the LBX1 gene. In a recent exome sequencing study of a European population, rare variants in Fibrillin 1 and 2 were found to contribute to scoliosis [8]. We could not replicate these findings (data not shown).…”

“…Recent genome-wide association studies have identified common genetic variants close to, or within, the ladybird homeobox 1 (LBX1), cell adhesion molecule L1-like (CHL1), and G protein-coupled receptor 126 (GPR126) genes, as well as an intergenic variant on 17q, in Asian and Caucasian populations [4][5][6][7]. One exome sequencing study has identified novel, rare variants associated with idiopathic scoliosis in the Fibrillin 1 and 2 genes in a European population [8]. However, these variants explain only a small part of the heritability of this disorder.…”

Genetics and pathogenesis of idiopathic scoliosis

“…They further sequenced exons of HSPG in 100 independent IS patients and found 21 other potentially damaging variants in HSPG . Buchan et al [48] exome-sequenced a cohort of 91 individuals with severe IS and compared the results with 337 controls. Using a gene burden analysis, they found that variants within the fibrillin 1 and 2 genes were associated with IS.…”

Adolescent idiopathic scoliosis: evidence for intrinsic factors driving aetiology and progression

“…However, recent genetic studies have provided preliminary evidence that skeletal muscle dysfunction could be a contributory factor in AIS susceptibility: Firstly, rare variants in fibrillin-1 (FBN1) and fibrillin-2 (FBN2) have been found to be associated with severe AIS [6]. FBN1 and 2 are glycoproteins that form key components of skeletal muscle myofibrillar structure.…”