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Hum Mol Genet. 2014 Oct 1;23(19):5271-82. doi: 10.1093/hmg/ddu224. Epub 2014 May 15.

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

Author information

1
Department of Genetics.
2
Department of Orthopaedic Surgery.
3
Department of Psychiatry.
4
Department of Neurology.
5
Department of Pediatrics.
6
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
Department of Orthopaedic Surgery, University of Colorado, Denver, CO 80202, USA.
8
Department of Orthopaedic Surgery, University of Iowa, Iowa City, IA 52242, USA.
9
The Chinese University of Hong Kong, Hong Kong, China and.
10
Department of Orthopaedic Surgery St. Louis Shriners Hospital for Children, St. Louis, MO 63131, USA.
11
Department of Orthopaedic Surgery Department of Neurology Department of Pediatrics, gurnettc@neuro.wustl.edu.

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.

PMID:
24833718
PMCID:
PMC4159151
DOI:
10.1093/hmg/ddu224
[Indexed for MEDLINE]
Free PMC Article

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