摘要
目的探讨经二代测序确诊的NF1基因突变致Ⅰ型神经纤维瘤病患儿的临床表型,同时总结NF1基因突变的遗传学特点。方法回顾性分析2017年12月至2019年10月就诊于郑州大学附属儿童医院神经内科的12例Ⅰ型神经纤维瘤病患儿的临床资料,采用二代测序方法对先证者进行NF1基因进行测序并对其家系成员进行一代Sanger验证,对基因突变特点进行分析,并总结其临床特征。结果在12例确诊为Ⅰ型神经纤维瘤病的患儿中,男女比例为11∶1,就诊年龄为7个月~11岁。临床表型中12例患儿均有牛奶咖啡斑,发病年龄为出生时至2岁,其中5例伴腋窝雀斑、2例伴皮肤神经纤维瘤;6例患儿有癫痫发作,发病年龄为5个月~5岁10个月,其中成串痉挛发作2例、全面性强直-阵挛发作2例、典型失神发作1例、局灶性发作1例,抗癫痫药物控制发作疗效较好;1例患儿有剧烈头痛伴呕吐。12例患儿共有5种基因突变形式,1例为NF1基因整体杂合缺失;3例错义突变,分别为c.7867C>A(p.L2623I)、c.7855C>A(p.L2619I)和c.7792C>A(p.L2598I);3例移码突变为c.3162delC(p.N1054Nfs*8)、c.540dupA(p.Q181Tfs*20)和c.2027dupA(p.V679Pfs*21);3例无义突变为c.1467T>A(p.Y489X,2351)、c.1318 C>T(p.R440X,2400)和c.1411C>T(p.K471X,2369);2例剪切突变为c.2326-2(IVS10)G>C和c.1186-1(IVS10)G>C。9例为自发突变,另1例来源于父亲,2例来源于母亲。其中c.7867C>A(p.L2623I)、c.7855C>A(p.L2619I)、c.3162delC(p.N1054Nfs*8)、c.1411C>T(p.K471X,2369)、c.2326-2(IVS10)G>C、c.1186-1(IVS10)G>C均为未报道的新生突变。结论Ⅰ型神经纤维瘤由NF1基因突变引起,早期临床表现多为牛奶咖啡斑,部分有癫痫发作。临床有多处牛奶咖啡斑伴癫痫发作的患者应尽早行基因分析确诊。
Objective To investigate the clinical phenotype and summarize the genetic characteristics of children with neurofibromatosis type 1(NF1)diagnosed by next-generation sequencing.Methods The clinical data of 12 children with NF1 who were admitted to the Department of Neurology of the Children's Hospital Affiliated to Zhengzhou University from December 2017 to October 2019 were retrospectively analyzed.The next-generation sequencing method was used to sequence the NF1 gene of the probands and the mutations were verified by PCR-Sanger sequencing.Results Among the 12 children diagnosed with NF1(male:female=11:1),who aged from seven months to 11 years old,the main complaints were seizures and skin with café-au-lait spots.Five children were found with freckles in axillae,and two with cutaneous neurofibroma.Six cases had seizures,two children suffered spastic seizures,two with generalized tonic-clonic seizures,one with typical absence seizure,one with focal seizure,one case had severe headache and vomiting.Fortunately for the children with seizures,anti-epileptic drugs had a good prognosis.There were five mutation types detected in 12 cases,including one case of loss of overall heterozygosity in NF1 gene;three missense mutations:c.7867C>A(p.L2623I),c.7855C>A(p.L2619I)and c.7792C>A(p.L2598I);three frameshift mutations:c.3162delC(p.N1054Nfs*8),c.540dupA(p.Q181Tfs*20)and c.2027dupA(p.V679Pfs*21);three nonsense mutations:c.1467T>A(p.Y489X,2351),c.1318C>T(p.R440X,2400)and c.1411C>T(p.K471X,2369);two splicing mutations:c.2326-2(IVS10)G>C and c.1186-1(IVS10)G>C.Nine children were found with spontaneous mutations,one case was inherited from the father,and two cases were inherited from the mother.c.7867C>A(p.L2623I),c.7855C>A(p.L2619I),c.3162delC(p.N1054Nfs*8),c.1411C>T(p.K471X,2369),c.2326-2(IVS10)G>C,c.1186-1(IVS10)G>C were unreported mutations in literature.Conclusions NF1 is caused by NF1 gene mutation.The early clinical manifestations of children with NF1 defect presented with café-au-lait spots,and some suffered seizures.For patients with multiple café-au-lait spots and seizures in the clinic,genetic analysis should be performed as soon as possible to confirm the diagnosis.
作者
梅道启
梅世月
陈国洪
王媛
王潇娜
唐志慧
陈晓轶
李东晓
张耀东
Mei Daoqi;Mei Shiyue;Chen Guohong;Wang Yuan;Wang Xiaona;Tang Zhihui;Chen Xiaoyi;Li Dongxiao;Zhang Yaodong(Department of Neurology,Children's Hospital Affiliated to Zhengzhou University,Henan Children's Hospital,Zhengzhou Children's Hospital,Zhengzhou 450018,China;Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases,Henan Engineering Research Center of Childhood Neurodevelopment,Zhengzhou 450018,China)
出处
《中华神经科杂志》
CAS
CSCD
北大核心
2020年第11期910-917,共8页
Chinese Journal of Neurology
基金
国家自然科学基金资助项目(81701125,81901387)
河南省科技攻关项目(2018020633,2018020603,2018020616)
河南省高等学校重点科研项目计划(18A310029)
河南省儿童神经发育工程研究中心开放课题(SG201907)。
