家族性巨大型牙骨质瘤家系致病基因新发突变和临床表型分析  

Identification of a de novo mutation in ANO5 by whole exome sequencing and clinical phenotype of familial gigantiform cementoma

作　　者：李欣 王周阳 秦兴军[1] LI Xin;WANG Zhou-yang;QIN Xing-jun(Department of Oromaxillofacial Head and Neck Oncology,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,College of Stomatology,Shanghai Jiao Tong University,National Center for Stomatology,National Clinical Research Center for Oral Diseases,Shanghai Key Laboratory of Stomatology.Shanghai 200011,China)

机构地区：[1]上海交通大学医学院附属第九人民医院口腔颌面-头颈肿瘤科,上海交通大学口腔医学院,国家口腔医学中心,国家口腔疾病临床医学研究中心,上海市口腔医学重点实验室,上海200011

出　　处：《中国口腔颌面外科杂志》2022年第4期360-365,共6页China Journal of Oral and Maxillofacial Surgery

基　　金：国家自然科学基金(82071099);上海交通大学医学院附属第九人民医院交叉基金(JYJC202007);上海交通大学医学院附属第九人民医院罕见病专项基金(JYHJB01)。

摘　　要：目的:应用全外显子测序技术对家族性巨大型牙骨质瘤(familial gigantiform cementoma,FGC)家系进行测序,筛选致病基因及突变,并探讨基因型与临床表型的关系。方法:纳入以颌骨畸形、下肢长骨骨折为主要表现的1个FGC家系9例患者,评估患者临床表现、骨影像学、骨密度、骨转换相关生化等指标。提取9例患者及家系中14名未患病者外周血基因组DNA,进行全基因组外显子捕获及高通量测序,通过生物信息学分析、确定突变位点,利用Sanger测序法对384名未患FGC且无此疾病家族史的受试者进行验证。结果:FGC主要表型为上、下颌骨4个象限内均存在弥漫性多发病灶,以下颌骨体前部尤为严重,颌骨畸形明显;并伴有全身骨密度下降,常因轻微外力导致多次下肢长骨骨折。全外显子测序发现,所有患者均存在ANO5(c.1538C>T,p.Thr513Ile)杂合突变,该突变影响ANO5蛋白功能与结构。结论:FGC是罕见的常染色体显性遗传疾病,中国FGC患者以颌骨畸形、下肢长骨骨折、骨密度降低为主要表型。ANO5基因突变是目前唯一致病基因,扩展了对FGC表型和致病基因突变型的认识。PURPOSE:To develop an approach based on whole exome sequencing(WES)to explore the correlation between genotype and clinical phenotype of a Chinese familial gigantiform cementoma(FGC)family caused by a mutation in ANO5 gene.METHODS:Nine patients from a Chinese FGC family with facial deformities and lower limb fractures were included.The clinical manifestations,skeletal radiographic features,bone mineral density(BMD),and bone turnover biomarkers were investigated.Peripheral blood from 9 patients and 14 controls within the family was collected,and WES was performed.By using filtering strategy,the candidate genes were sequenced and further validated by PCR and Sanger sequencing in the unaffected individuals within the family and 384 healthy control subjects.RESULTS:The major manifestations of Chinese FGC patients were representative multiquadrant and expansive deformities involving the mandible and maxilla,especially severe in the anterior mandible with diffuse osteopenia bone loss and several fractures in the lower limbs.Sequencing results showed that there was a missense,heterozygous mutation in ANO5(c.1538C>T,p.Thr513Ile)in all affected individuals,that affected the folding,structure and function of ANO5.CONCLUSIONS:FGC is a rare autosomal dominant hereditary disease caused by ANO5 mutations,with severe facial deformity,long bone fractures and low BMD as main characteristics of Chinese’patients.The first and a novel missense mutation of ANO5 was identified,which extended the phenotypic and genetic spectrum of FGC.

关 键 词：家族性巨大型牙骨质瘤 ANO5基因 遗传突变 表型 基因型 

分 类 号：R739.8[医药卫生—肿瘤]