CANT1基因变异导致Desbuquois发育不良Kim变异型临床特征与遗传学分析

Clinical characteristics and genetic analysis of Desbuquois dysplasia Kim type caused by CANT1 mutation

目的通过分析1例手部外观无异常的汉族Desbuquois发育不良(DBQD)患儿的临床与遗传学特征,进一步拓展中国人群DBQD的表型和基因变异谱。方法收集DBQD患儿的临床资料,采用全外显子组家系测序(Trio-WES)检测患儿及其父母的基因变异情况,采用生物信息学分析和晶体结构分析评估变异位点的生物危害性,并采用Sanger测序进行验证。通过文献回顾总结DBQD的临床特征和基因变异谱。结果患儿具有特殊容貌(扁平圆脸、眼球突出、鼻梁低平)、发育迟缓、脊柱侧弯和双足疼痛等临床特征,但手部外观无异常。Trio-WES检测结果显示,患儿CANT1基因发生纯合变异c.494T>C(p.Met165Thr),其父母为该变异位点的杂合携带者。SIFT、Polyphen-2和Mutation Taste在线软件预测c.494T>C变异可对蛋白或蛋白产物造成有害影响。Sanger测序证实变异位点存在。晶体结构预测提示c.494T>C(p.Met165Thr)变异可能会导致蛋白局部结构稳定性降低,进而影响蛋白功能。根据患儿手部特征、临床表型和基因检测结果诊断为DBQD-Kim变异型。通过文献回顾分析41例CANT1基因变异导致的DBQD患者的特征,共发现32个CANT1基因变异,其中错义变异15个、移码变异11个、无义变异3个、非编码区变异3个、拷贝数缺失变异1个;在DBQD 1型患者中,CANT1蛋白第300号精氨酸变异(p.Arg300His或p.Arg300Cys)发生频率最高;而Kim变异型患者主要以第156号丝氨酸变异(p.Ser156Phe)和第226号缬氨酸变异(p.Val226Met)为主。结论DBQD-Kim变异型患儿广泛的骨骼异常表现可能是由CANT1基因纯合变异所致。结合临床表型和基因检测结果可明确诊断DBQD,并进行分型。

Objective By analyzing the clinical and genetic characteristics of a Han patient with Desbuquois dysplasia(DBQD)without abnormal hand appearance,the phenotypic and genetic variation spectrum of DBQD in Chinese population has been further expanded.Methods The clinical data of the patient with DBQD were collected,and the genetic mutations of the patient and his parents were determined by trio-whole exome sequencing(Trio-WES).Bioinformatics analysis and crystal structure analysis were used to analyze the biohazard of mutation,and Sanger sequencing was used to verify.The clinical characteristics and genetic variation spectrum of DBQD were summarized through literature review.Results The patient had special features(flat round face,exophthalmos and low bridge of nose),growth retardation,scoliosis and foot pain,but the appearance of hands was normal.The results of Trio-WES showed that the homozygous mutation of the CANT1 gene was c.494T>C(p.Met165Thr),and the parents were heterozygous carriers of the mutation.SIFT,Polyphen-2 and Mutation Taste online softwares predicted that c.494T>C can cause harmful effects on protein or protein products.Sanger sequencing confirmed the existence of mutation.The prediction of crystal structure suggested that c.494T>C(p.Met165Thr)may lead to the decrease of local structural stability of protein and affect the function of protein.The patient was diagnosed as DBQD-Kim type according to the hand characteristics,clinical phenotypic characteristics and gene determination results.Through literature review and the analysis of 41 patients with DBQD caused by CANT1 gene mutation,32 CANT1 gene mutations were found,including 15 missense mutations,11 frameshift mutations,3 nonsense mutations,3 noncoding mutations and 1 copy number deletion mutation.Among patients with DBQD 1 type,the frequency of arginine mutation(p.Arg300His or p.Arg300Cys)of CANT1 protein 300 was the highest.The Kim type patients were mainly serine 156(p.Ser156Phe)and valine 226(p.Val226Met).Conclusions The extensive skeletal abnormalities in children with DBQD-Kim type may be caused by homozygous mutation of CANT1 gene.Combined with clinical phenotype and gene determination results,DBQD can be clearly diagnosed and classified.