Buchan Jillian G, Alvarado David M, Haller Gabe E, Cruchaga Carlos, Harms Matthew B, Zhang Tianxiao, Willing Marcia C, Grange Dorothy K, Braverman Alan C, Miller Nancy H, Morcuende Jose A, Tang Nelson Leung-Sang, Lam Tsz-Ping, Ng Bobby Kin-Wah, Cheng Jack Chun-Yiu, Dobbs Matthew B, Gurnett Christina A
Department of Genetics.
Department of Orthopaedic Surgery.
Hum Mol Genet. 2014 Oct 1;23(19):5271-82. doi: 10.1093/hmg/ddu224. Epub 2014 May 15.
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.
青少年特发性脊柱侧凸（AIS）在3%的儿童中导致脊柱畸形。尽管有很强的遗传基础，但很少有基因与AIS相关，其发病机制仍知之甚少。在一项使用外显子序列数据的全基因组罕见变异负担分析中，我们确定原纤蛋白-1（FBN1）是与AIS最显著相关的基因。基于这些结果，我们对总共852例AIS病例和669例对照进行了FBN1和相关基因原纤蛋白-2（FBN2）的测序。在欧洲血统的个体中，与内部对照（2.4%）相比，严重受累的AIS病例中FBN1和FBN2的罕见变异更为富集（7.6%）（OR = 3.5，P = 5.46×10⁻⁴），与外显子测序计划对照（2.3%）相比也是如此（OR = 3.5，P = 1.48×10⁻⁶）。AIS病例的脊柱侧凸严重程度与FBN1和FBN2罕见变异相关（P = 0.0012），并在一个独立的汉族队列中得到重复验证（P = 0.0376），这表明罕见变异可能有助于预测侧弯进展。临床评估显示，大多数携带FBN1罕见变异的AIS病例不符合马凡综合征的诊断标准，尽管这些变异与身材高大（P = 0.0035）和转化生长因子β通路的上调有关。总体而言，这些结果扩展了我们对原纤蛋白相关疾病的定义，将AIS纳入其中，并为严重AIS的诊断和治疗开辟了新策略。
