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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.

SUBMITTER: Buchan JG

PROVIDER: S-EPMC4159151 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Buchan Jillian G JG Alvarado David M DM Haller Gabe E GE Cruchaga Carlos C Harms Matthew B MB Zhang Tianxiao T Willing Marcia C MC Grange Dorothy K DK Braverman Alan C AC Miller Nancy H NH Morcuende Jose A JA Tang Nelson Leung-Sang NL Lam Tsz-Ping TP Ng Bobby Kin-Wah BK Cheng Jack Chun-Yiu JC Dobbs Matthew B MB Gurnett Christina A CA

Human molecular genetics 20140515 19

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 individu ...[more]

PMID: 24833718

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Project description:BackgroundDespite more than a century of dedicated research, the etiology and pathogenesis of adolescent idiopathic scoliosis (AIS) remain unclear. By definition, 'idiopathic' implies an unknown cause. Nevertheless, many abnormalities concomitant to AIS have been described, often with the suggestion that these abnormalities are related to etio-pathogenesis. Insight in the concomitant abnormalities may assist in improving the understanding of the etiological pathways of AIS. We aimed to systematically review and synthesize available studies on abnormalities concomitant to AIS.MethodsOriginal studies comparing untreated AIS patients with healthy adolescents on abnormalities other than the deformity of the spine were retrieved from PubMed and Embase. We followed PRISMA guidelines and to quantify the relationship between each abnormality and AIS we used a best-evidence-syntheses for relating risk-of-bias to consistency of effect sizes.ResultsWe identified 88 relevant citations, forty-seven carried high risk-of-bias and twenty studies did not report quantitative data in a sufficient manner. The remaining twenty-one publications failed to report data from before initiation of the deformity and blind assessments. These cross-sectional studies provided data on fourteen abnormalities concomitant to AIS. With our best-evidence-syntheses we were unable to find both strong evidence and a consistent pattern of occurrence for AIS and any of these abnormalities. From moderate risk-of-bias studies a relatively consistent pattern of occurrence for AIS and impaired gait control (4 studies; 155 subjects; Cohen's d = 1.00) and decreased bone mineral density (2 studies; 954 subjects; Cohen's d =?-0.83) was found. For nine abnormalities a consistent pattern of occurrence with AIS was found, but the evidence for these was weak.ConclusionsBased on the available literature, strong evidence is lacking for a consistent pattern of occurrence of AIS and any abnormality. The relevance for understanding the multifactorial etiology of AIS is very limited.

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

Publications

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

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