NPC1基因复合杂合突变致尼曼-匹克病C型一家系  

A family of Niemann-Pick disease type C caused by compound heterozygous mutations in NPC1 gene

作　　者：李海江[1] 唐春艳[1] 钟莲梅[1] Li Haijiang;Tang Chunyan;Zhong Lianmei(Department of Neurology,the First Affiliated Hospital of Kunming Medical University,Provincial Clinical Research Center for Neurological Diseases,Kunming 650032,China)

机构地区：[1]昆明医科大学第一附属医院神经内科、云南省神经系统疾病临床医学研究中心,昆明650032

出　　处：《中华神经科杂志》2023年第9期986-991,共6页Chinese Journal of Neurology

基　　金：云南省重大科技专项计划(202102AA100061);云南省科技计划项目-省基础研究计划(昆医联合专项)(202201AY070001-090)。

摘　　要：目的报道NPC1基因新发复合杂合突变致尼曼-匹克病C型一家系的临床及遗传学特点,提高临床医师对该病的认识水平。方法对云南省昆明医科大学第一附属医院神经内科2020年收治的1个非近亲结婚家系中的2例患者进行详细的神经科体格检查,提取外周血DNA,应用二代测序技术对患者进行全外显子测序,结合Sanger测序对患者家系进行一代验证,应用软件对突变位点进行分析。结果该家系呈常染色体隐性遗传,2例患者的发病年龄不同,先证者9岁起病,主要表现为:构音不良、吞咽困难、认知障碍、共济失调、双侧锥体束损害、垂直核上凝视麻痹和脾脏肿大。先证者弟弟临床表型与患者相似,但比患者更为严重,发病年龄更早,婴幼儿期发病,伴有严重的精神运动发育迟缓。全外显子组测序结果显示,两兄弟均携带NPC1基因的两种罕见变异:c.352_353del,p.Gln119ValfsTer8和c.593A>G,p.Asn198Ser。Sanger测序验证结果提示复合杂合突变分别来源于先证者的父母。根据美国医学遗传学与基因组学学会指南,上述变异评级分别为致病和疑似致病变异。该家系患者携带的c.593A>G,p.Asn198Ser变异为未报道的新变异。先证者从症状出现开始延迟诊断7年,服用麦格司他1年后吞咽困难、共济失调及眼球垂直运动障碍等症状有明显的好转。结论该家系患者的临床表型符合尼曼-匹克病C型的临床表型,NPC1基因复合杂合突变(c.352_353del和c.593A>G)为该家系的遗传学病因。Objective To report the clinical and genetic characteristics of a family with Niemann-Pick disease type C caused by novel compound heterozygous mutations in the NPC1 gene to improve the clinicians′recognition of the disease.Methods Two patients from the family with non-consanguineous marriages admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University in 2020 were examined in detail.Peripheral blood DNA was extracted,and whole exome sequencing was performed on the patients,combined with Sanger sequencing for verification.The mutation and protein function predictor softwares were applied to analyze the mutation sites.Results The inheritance was autosomal recessive in this family.The onset age of the proband was 9 years,and the main clinical manifestations were dysarthria,dysphagia,cognitive impairment,ataxia,bilateral pyramidal tract impairment,vertical supranuclear gaze palsy and splenomegaly.The clinical phenotype of the proband′s younger brother was similar to that of the proband,but it was more severe than that of the proband.The younger brother of the proband had an earlier age of onset and severe psychomotor retardation.Whole exome sequencing showed that both brothers carried 2 rare variants of NPC1 gene:1 pathogenic,stop gain at c.352_353del,p.Gln119ValfsTer8,and a missense change,c.593A>G,p.Asn198Ser,of suspected pathogenic.Sanger sequencing confirmed that compound heterozygous mutations were derived from the proband′s parents.According to the American College of Medical Genetics and Genomics guidelines,the above variants were rated as pathogenic and suspected pathogenic,respectively.And the c.593A>G,p.Asn198Ser mutation found in this family was a novel one which had not been reported yet.The proband had delayed diagnosis for 7 years from the onset of symptoms.After taking megastat for 1 year,the symptoms of dysphagia,ataxia and vertical eye movement disorder were significantly improved.Conclusions The clinical phenotype of the pedigree was consistent with

关 键 词：尼曼-匹克病 C型 NPC1基因 脾大 基因变异 

分 类 号：R596[医药卫生—内科学] R747.9[医药卫生—临床医学]