Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis.
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.
Department of Genetics.
Jillian G
JG
Buchan
Department of Orthopaedic Surgery.
David M
DM
Alvarado
Department of Orthopaedic Surgery.
Gabe E
GE
Haller
Department of Psychiatry.
Carlos
C
Cruchaga
Department of Neurology.
Matthew B
MB
Harms
Department of Psychiatry.
Tianxiao
T
Zhang
Department of Pediatrics.
Marcia C
MC
Willing
Department of Pediatrics.
Dorothy K
DK
Grange
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Alan C
AC
Braverman
Department of Orthopaedic Surgery, University of Colorado, Denver, CO 80202, USA.
Nancy H
NH
Miller
Department of Orthopaedic Surgery, University of Iowa, Iowa City, IA 52242, USA.
Jose A
JA
Morcuende
The Chinese University of Hong Kong, Hong Kong, China and.
Nelson Leung-Sang
NL
Tang
The Chinese University of Hong Kong, Hong Kong, China and.
Tsz-Ping
TP
Lam
The Chinese University of Hong Kong, Hong Kong, China and.
Bobby Kin-Wah
BK
Ng
The Chinese University of Hong Kong, Hong Kong, China and.
Jack Chun-Yiu
JC
Cheng
Department of Orthopaedic Surgery St. Louis Shriners Hospital for Children, St. Louis, MO 63131, USA.
Matthew B
MB
Dobbs
Department of Orthopaedic Surgery Department of Neurology Department of Pediatrics, gurnettc@neuro.wustl.edu.
Christina A
CA
Gurnett
D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002648:Child; D005260:Female; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics*; D016017:Odds Ratio; D064170:Paraspinal Muscles / Q000378:metabolism; D010766:Phosphorylation; D044469:Racial Groups / Q000235:genetics; D012600:Scoliosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D051899:Smad2 Protein / Q000378:metabolism; D055815:Young Adult; D054392:Adipokines
D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins; D051899:Smad2 Protein; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human