Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis
Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis
复制标题
外显子组测序分析确定了青少年特发性脊柱侧凸中常见的寡基因参与和 FLNB 变异。
DOI：
10.1136/jmedgenet-2019-106411
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发表时间：
2020-06-01
影响因子：
4
通讯作者：
Zhou, Xuhui
中科院分区：
文献类型：
--
作者：
Jiang, Heng;Liang, Shulun;Zhou, Xuhui
研究背景青少年特发性脊柱侧凸（adolescentidiopathicscoliosis，AIS）是一种遗传异质性疾病，以脊柱三维畸形为特征，无先天性脊柱畸形或神经肌肉骨骼疾病。AIS相关基因的临床变异性和不完全突变性表明AIS是一种寡基因遗传性疾病，我们的目的是探索这种疾病的寡基因性质，并确定新的AIS基因。方法我们分析了AIS相关基因内罕见的破坏性变异，通过使用外显子组测序在40个AIS三重奏和183个散发性患者。5个人在FLNB基因中携带罕见的破坏性变异。与对照组相比，患者表现出更频繁的寡聚性。在基于基因的负荷测试中，顶部信号驻留在FLNB中。在功能研究中，我们发现AIS相关的FLNB变体改变了蛋白质的构象和亚细胞定位及其与AIS中涉及的其他蛋白质（TTC 26和OFD 1）的相互作用。最令人信服的证据的寡基因的基础是，罕见的破坏性变异的数量被确认为曲线进展的独立预后因素在考克斯regression analysis.ConclusionOur数据表明，AIS是一种寡基因疾病，并确定FLNB作为AIS的易感基因。
BackgroundAdolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait.ObjectiveWe aimed to explore the oligogenic nature of this disease and identify novel AIS genes.MethodsWe analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients.ResultsMultiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein's conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis.ConclusionOur data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.