Charng Wu-Lin, Haller Gabe, Whittle Julia, Nikolov Momchil, Avery Addison, Morcuende Jose, Giampietro Philip, Raggio Cathy, Miller Nancy, Justice Anne E, Strande Natasha T, Seeley Mark, Bodian Dale L, Wise Carol A, Sepich Diane S, Dobbs Matthew B, Gurnett Christina A
Department of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
Department of Neurosurgery, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
J Med Genet. 2025 Apr 29. doi: 10.1136/jmg-2024-110586.
Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.
To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. function was investigated in null mutant zebrafish.
Rare variants were enriched in 84 genes, including (Noonan syndrome), (Marfan syndrome) and in individuals with severe AIS. , which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the locus in zebrafish resulted in increased bone mineral density.
We broadened the phenotype associated with and variants and identified as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of missense variants with AIS.
脊柱侧弯是最常见的儿童脊柱畸形。超过80%的脊柱侧弯是特发性的，且出现在青少年生长突增期。对于进行性青少年特发性脊柱侧弯（AIS）患者，通常需要进行脊柱融合手术，而严重疾病（此处定义为侧弯>35度）的遗传风险因素在很大程度上尚不清楚。
为了探究罕见变异在严重AIS中的作用，将1221例AIS患者的外显子序列数据与1397例欧洲血统内部对照以及56885例gnomAD非芬兰欧洲对照进行了比较。对优先基因中的变异进行了额外家庭成员的分离分析。使用盖辛格MyCode队列进行了一项复制研究。在纯合突变斑马鱼中研究了功能。
84个基因中富集了罕见变异，包括严重AIS个体中的（努南综合征）、（马凡综合征）和。先前与关节活动过度相关的，在4.0%的AIS个体中存在错义变异，而对照中为2.3%（p = 0.00764，OR = 1.78）。变异在五个外显率不完全的多重家庭中与AIS分离。此外，盖辛格MyCode队列中的罕见变异也与脊柱侧弯相关（p = 0.0002，OR = 3.6）。斑马鱼中位点的破坏导致骨矿物质密度增加。
我们拓宽了与和变异相关的表型，并确定为与严重AIS相关的新基因。骨矿物质密度或关节活动过度的机制改变可能解释错义变异与AIS的关联。
