KMT2D基因致病新变异引起的歌舞伎综合征表型分析  

Phenotypic analysis of Kabuki syndrome caused by new pathogenic variation of KMT2D gene

作　　者：卢慧敏 段丽芬[2] 叶磊[2] 王晓辉[1] 边成 褚嘉祐[1] 杨昭庆[1] LU Huimin;DUAN Lifen;YE Lei;WANG Xiaohui;Bian Cheng;CHU Jiayou;YANG Zhaoqing(Department of Medical Genetics,Institute of Medical Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Kunming,Yunnan 650118,China;Epilepsy Center,Kunming Children’s Hospital,Kunming,Yunnan 650034,China)

机构地区：[1]中国医学科学院&北京协和医学院医学生物学研究所医学遗传学研究室,云南昆明650118 [2]昆明市儿童医院癫痫中心,云南昆明650034

出　　处：《中国优生与遗传杂志》2022年第5期803-807,共5页Chinese Journal of Birth Health & Heredity

基　　金：云南省应用基础研究联合基金专项(202001AY070001-273);云南省高层次卫生健康技术人才项目(L-2018003);昆明市卫生科技人才培养项目暨“十百千”工程培养计划(2021-SW(省)-23)。

摘　　要：目的对表现出特殊面容、生长发育落后、心血管形态异常等疑似歌舞伎脸谱综合征(KS)表型的1例主动脉弓断裂患儿进行临床和遗传学检测,明确患病病因。方法获取病患病史及临床检测数据,并提取先证者及其父母血液DNA进行全外显子组测序,结合生物信息学分析筛选致病突变,通过Sanger DNA测序验证致病突变在家系中的遗传方式。结果患儿为9月龄男婴,主要临床表现为特殊面容、主动脉弓离断(A型)、二尖瓣瓣上隔膜、主动脉瓣二瓣化畸形、卵圆孔未闭等,全外显子组测序结果显示患者携带KMT2D基因(NM_003482)c.16028delC变异(p.pro5343LeufsTer13),为阅读框移码变异,患儿确诊为由KMT2D基因突变导致KSⅠ型,为常染色体显性遗传。Sanger DNA测序结果显示患儿父亲、母亲及哥哥均未携带该突变,表明该突变为新发变异。根据ACMG变异解读标准,该基因变异分类为PVS1+PS2+PM2,属于致病突变。结论KMT2D基因c.16028delC(p.pro5343LeufsTer13)移码变异为该患儿歌舞伎综合征的致病基因突变,该变异位点之前未见报道。本研究结果表明,即便患儿早期仅仅出现不典型的疑似KS症状时,也应该尽早进行基因检测和临床检查,实现早诊断和早干预。本研究进一步丰富了歌舞伎综合征的基因突变谱和临床表现数据,为该病的诊断和遗传咨询提供了参考依据。Objective To identify the genetic cause of a child with suspected Kabuki syndrome(KS)phenotypes including special facial features,growth retardation,and cardiovascular abnormalities,clinical and genetic detection were used.Methods The medical history and clinical detection data were collected.The blood DNA of the proband and his parents were extracted.Whole exome sequencing(WES)and bioinformatic analysis were used to identify pathogenic mutations.And Sanger DNA sequencing was used to verified the genetic way of pathogenic mutations in the family.Results A 9-month-old male child presented clinical manifestations including special facial features,interrupted aortic arch(type A),diaphragm on the mitral valve,aortic valve bivalve deformity,patent foramen ovale,and so on.The whole exome sequencing results showed that the patient carried KMT2D gene mutation c.16028delC(P.ro5343leufster13),which was a frameshift mutation.The child was diagnosed as KS type I caused by KMT2D gene mutation,which was autosomal dominant.Sanger DNA sequencing results showed that the father,mother and brother of the proband did not carry the KMT2D mutation,indicating that this mutation was a de novo mutation.According to the ACMG mutation interpretation standard,the mutation was classified as PVS1+PS2+PM2,and determined as a pathogenic mutation of Kabuki syndrome.Conclusion The frameshift mutation c.16028delC(P.ro5343leUFster13)of KMT2D gene is the pathogenic cause of Kabuki syndrome of the child in the present study.The mutation was reported as the pathogenic mutation site of KS for the first time.Our study enriched the gene mutation spectrum of Kabuki syndrome and provided more reference for the diagnosis and genetic counseling of the disease.Even only atypical KS symptoms appear in early neonates,genetic and clinical testes should be considered to early diagnosis and intervention.

关 键 词：歌舞伎综合征 先天性心脏病 主动脉弓断裂 KMT2D基因 新发变异 

分 类 号：R596[医药卫生—内科学]