title: Targeted next-generation sequencing reveals multiple deleterious variants in OPLL-associated genes.
abstract: Ossification of the posterior longitudinal ligament of the spine (OPLL), which is characterized by ectopic bone formation in the spinal ligaments, can cause spinal-cord compression. To date, at least 11 susceptibility genes have been genetically linked to OPLL. In order to identify potential deleterious alleles in these OPLL-associated genes, we designed a capture array encompassing all coding regions of the target genes for next-generation sequencing (NGS) in a cohort of 55 unrelated patients with OPLL. By bioinformatics analyses, we successfully identified three novel and five extremely rare variants (MAF < 0.005). These variants were predicted to be deleterious by commonly used various algorithms, thereby resulting in missense mutations in four OPLL-associated genes (i.e., COL6A1, COL11A2, FGFR1, and BMP2). Furthermore, potential effects of the patient with p.Q89E of BMP2 were confirmed by a markedly increased BMP2 level in peripheral blood samples. Notably, seven of the variants were found to be associated with the patients with continuous subtype changes by cervical spinal radiological analyses. Taken together, our findings revealed for the first time that deleterious coding variants of the four OPLL-associated genes are potentially pathogenic in the patients with OPLL.
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung &Blood Vessel Disease, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung &Blood Vessel Disease, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Fengshan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Shengfa
authors.initials: S
authors.lastname: Pan
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Yinze
authors.initials: Y
authors.lastname: Diao
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Orthopaedic Department, Institute of Spinal Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung &Blood Vessel Disease, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000328:Adult; D000368:Aged; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D024161:Collagen Type XI / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017846:Longitudinal Ligaments / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017887:Ossification of Posterior Longitudinal Ligament / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D013131:Spine / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D014057:Tomography, X-Ray Computed
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C499319:COL11A2 protein, human; C553839:Col6a1 protein, human; D024142:Collagen Type VI; D024161:Collagen Type XI; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1