中国医学科学院学报

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中国医学科学院学报

中国医学科学院学报 ›› 2021, Vol. 43 ›› Issue (1): 25-31.doi: 10.3881/j.issn.1000-503X.12629

• 论著 • 上一篇    下一篇

Klippel-Feil综合征的临床特征及遗传学分析

李子全1,2,耿墨钊1,2,赵森1,2,吴志宏2,仉建国1,2,3,吴南1,2,3,王以朋1,2,3()   

  1. 1中国医学科学院 北京协和医学院 北京协和医院 骨科 北京 100730
    2中国医学科学院 北京协和医学院 北京协和医院 北京市骨骼畸形遗传学研究重点实验室 北京 100730
    3中国医学科学院 北京协和医学院 北京协和医院 脊柱畸形大数据研究与应用重点实验室, 北京 100730
  • 收稿日期:2020-02-20 出版日期:2021-02-28 发布日期:2021-03-05
  • 通讯作者: 王以朋 E-mail:ypwang@vip.126.com
  • 基金资助:
    中国博士后科学基金(2020TQ0052);国家自然科学基金面上项目(81871746)

Clinical Characteristics and Genetic Analysis of Klippel-Feil Syndrome

LI Ziquan1,2,GENG Mozhao1,2,ZHAO Sen1,2,WU Zhihong2,ZHANG Jianguo1,2,3,WU Nan1,2,3,WANG Yipeng1,2,3()   

  1. 1Department of Orthopaedics, PUMC Hospital, CANS and PUMC, Beiig 10730 China
    2Beijing Key Laboratory for Genetic Research of Skeletal Deformity,PUMC Hospital, CANS and PUMC, Beiig 10730 China
    3Key Laboratory of Big Data for Spinal Deformities,PUMC Hospital,CAMS and PUMC,Beijing 100730,China
  • Received:2020-02-20 Online:2021-02-28 Published:2021-03-05
  • Contact: WANG Yipeng E-mail:ypwang@vip.126.com
  • Supported by:
    Supported by the China Postdoctoral Science Foundation(2020TQ0052);National Natural Sciences Foundation of China(81871746)

摘要:

目的 总结Klippel-Feil综合征(KFS)的临床特征,利用自主设计的多基因panel测序筛查KFS患者的可能致病基因,为疾病早期诊断及靶向治疗提供基础。方法 以2015年1月至2018年12月在北京协和医院明确KFS诊断的25例患者为研究对象,统计所有患者的流行病学信息、临床表现、体格检查及影像学资料,提取外周血DNA后进行多基因panel二代测序,并结合生物信息学分析探索KFS可能的致病突变。结果 25例KFS患者中,男15例,女10例,平均年龄(12.9±7.3)岁,颈椎活动受限是最常见的临床特征(12例,48%)。根据Samartzis分型,KFS Ⅲ型患者出现短颈(P=0.031)和颈椎活动受限(P=0.026)的比例明显高于KFS Ⅱ型和KFS Ⅰ型。Panel测序共在8例患者中检测到11种基因突变,包括COL6A1、COL6A2、CDAN1、GLI3、FLNB、CHRNG、MYH3、POR、TNXB,突变类型均为错义突变;未发现已报道的5种KFS致病基因(GDF6、MEOX1、GDF3、MYO18B和RIPPLY2)的突变。结论 长节段连续性颈椎融合畸形患者更易表现出短颈畸形、颈椎活动受限及临床三联征的表现,因此在临床中更应引起关注和密切随访。筛选出COL6A、CDAN1等与KFS相关的候选致病突变,扩展了KFS的已知突变谱,为进一步阐明疾病的发病机制提供参考。

关键词: Klippel-Feil综合征, 临床三联征, 伴发畸形, 多基因panel测序, 基因突变

Abstract:

Objective To summarize clinical characteristics and investigate possible pathogenic gene of Klippel-Feil syndrome(KFS)by the self-designed multigene panel sequencing,so as to decipher the molecular basis for early diagnosis and targeted therapy.Methods From January 2015 to December 2018,we consecutively recruited 25 patients who were diagnosed with KFS in Peking Union Medical College Hospital.The demographic information,clinical manifestations,physical examination and radiological assessments were analyzed.Multigene panel sequencing was performed after DNA extraction from peripheral blood.The possible pathogenic mutations of KFS were explored on the basis of bioinformatics analysis.Results The KFS cohort consisted of 25 patients,including 15 males and 10 females,with a mean age of(12.9±7.3)years.Limited cervical range of motion was the most common clinical feature(12 cases,48%).Based on the Samartzis classification,the proportion of patients suffered from short neck(P=0.031)and limited cervical range of motion(P=0.026)in type Ⅲ KFS was significantly higher than that in type Ⅱ and type Ⅰ KFS.Panel sequencing detected a total of 11 pathogenic missense mutations in eight patients,including COL6A1,COL6A2,CDAN1,GLI3,FLNB,CHRNG,MYH3,POR,and TNXB.There was no pathogenic mutation found in five reported pathogenic genes(GDF6,MEOX1,GDF3,MYO18B and RIPPLY2)associated with KFS.Conclusions Our study has shown that patients with multiple contiguous cervical fusions are more likely to manifest short neck,limited cervical range of motion,and clinical triad.Therefore,these patients need additional attention and follow-up.Our analysis highlights novel KFS-related genetic variants,such as COL6A and CDAN1,extending the spectrum of known mutations contributing to this syndrome and providing a basis for elucidating the pathogenesis of KFS.

Key words: Klippel-Feil syndrome, clinical triad, associated anomalies, multigene panel sequencing, gene mutation

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