RT Journal Article SR Electronic T1 Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 405 OP 413 DO 10.1136/jmedgenet-2019-106411 VO 57 IS 6 A1 Heng Jiang A1 Shulun Liang A1 Kai He A1 Jinghua Hu A1 Enjie Xu A1 Tao Lin A1 Yichen Meng A1 Jianquan Zhao A1 Jun Ma A1 Rui Gao A1 Ce Wang A1 Fu Yang A1 Xuhui Zhou YR 2020 UL http://jmg.bmj.com/content/57/6/405.abstract AB Background Adolescent 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.Objective We aimed to explore the oligogenic nature of this disease and identify novel AIS genes.Methods We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients.Results Multiple 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.Conclusion Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.