青少年起病的伴基底节区和小脑萎缩的低髓鞘化脑白质营养不良患者1例的TUBB4A基因变异分析  

Analysis of TUBB4A gene variant in a patient with adolescent-onset hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum

作　　者：应子璇 程曦 许晓泉[2] 马志 陈政宇 陈文[2] 秦朗 牛琦 Ying Zixuan;Cheng Xi;Xu Xiaoquan;Ma Zhi;Chen Zhengyu;Chen Wen;Qin Lang;Niu Qi(Department of Geriatrics,Division of Neurology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China;Department of Radiology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China)

机构地区：[1]南京医科大学第一附属医院老年神经科,南京210029 [2]南京医科大学第一附属医院放射科,南京210029

出　　处：《中华医学遗传学杂志》2023年第4期390-394,共5页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(82071434);江苏"六大人才高峰"高层次人才选拔培养项目(WSN-004)。

摘　　要：目的探讨1例青少年起病的伴基底节区和小脑萎缩的低髓鞘化脑白质营养不良(H-ABC)患者的临床特征与遗传学病因。方法选取2018年3月于南京医科大学第一附属医院就诊的1例H-ABC患者为研究对象。收集患者的临床资料,抽取患者及其父母的外周静脉血样,用全外显子组测序(WES)对患者进行检测,对候选变异进行Sanger测序家系验证和致病性分析。结果患者为31岁男性,表现为发育迟缓、认知下降及步态异常等。WES检测结果提示其TUBB4A基因存在c.286G>A杂合变异,Sanger测序结果显示患者父母均未携带该变异。经SIFT在线软件分析,该变异位点编码的氨基酸具有高度的进化保守性。该变异已被人类基因突变数据库(HGMD)收录,人群携带频率低。经PyMOL软件构建3D结构显示,该变异对编码蛋白结构及功能可能产生有害的影响。根据美国医学遗传学与基因组学学会(ACMG)相关指南,该变异被评级为可能致病性变异(PS2+PM2_Supporting)。结论TUBB4A基因c.286G>A(p.Gly96Arg)变异可能是H-ABC患者的遗传学病因。上述发现进一步丰富了TUBB4A基因的变异谱,为患者的早期确诊提供了依据。Objective To explore the clinical characteristics and genetic etiology of a patient with adolescent-onset hypomyelinated leukodystrophy with atrophy of basal ganglia and cerebellum(H-ABC).Methods A patient who was diagnosed with H-ABC in March 2018 at the First Affiliated Hospital of Nanjing Medical University was selected as the study subject.Clinical data was collected.Peripheral venous blood samples of the patient and his parents were collected.The patient was subjected to whole exome sequencing(WES).Candidate variant was verified by Sanger sequencing.Results The patient,a 31-year-old male,had manifested with developmental retardation,cognitive decline and abnormal gait.WES revealed that he has harbored a heterozygous c.286G>A variant of the TUBB4A gene.Sanger sequencing confirmed that neither of his parents has carried the same variant.Analysis with SIFT online software indicated the amino acid encoded by this variant is highly conserved among various species.This variant has been recorded by the Human Gene Mutation Database(HGMD)with a low population frequency.The 3D structure constructed by PyMOL software showed that the variant has a harmful effect on the structure and function of the protein.According to the guidelines formulated by the American College of Medical Genetics and Genomics(ACMG),the variant was rated as likely pathogenic.Conclusion The c.286G>A(p.Gly96Arg)variant of the TUBB4A gene probably underlay the hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum in this patient.Above finding has enriched the spectrum of TUBB4A gene variants and enabled early definitive diagnosis of this disorder.

关 键 词：低髓鞘化脑白质营养不良 基底节区和小脑萎缩 TUBB4A基因 新发变异 

分 类 号：R742[医药卫生—神经病学与精神病学]