伴基底核小脑萎缩的髓鞘形成低下一家系临床与 TUBB4A 基因突变分析

Abstract

目的：分析并确定一个伴基底核小脑萎缩的髓鞘形成低下（HABC）家系的临床特点与 TUBB4A基因突变特点，为本患者家庭提供准确的遗传咨询及产前诊断打基础，同时也为我国患儿在 HABC 疾病诊断方面提供经验。方法收集2014年12月就诊于北京大学第一医院儿科1例 HABC 先证者及其家系成员临床资料，进行临床特点分析，包括病史、体征、头颅 MRI、生化检查及代谢筛查；通过目标靶向-高通量测序技术对先证者及其家系成员进行遗传性白质脑病相关基因包筛查，对发现的遗传变异进行 Sanger 测序验证，明确基因突变类型，进行分子遗传学特点分析。结果临床特点：先证者以眼球震颤为首发症状，随后出现智力运动发育落后、肌张力异常及共济失调，头颅 MRI 提示脑白质髓鞘化不良、小脑及基底核区萎缩，临床诊断为 HABC。遗传学特点：先证者发现 TUBB4A 存在 c．974G ＞T 的杂合错义变异，该变异导致第325号氨基酸由 Trp 变为 Leu （p．Trp325Leu）。先证者之表型正常父母本位点为野生型。结论本研究中先证者临床表现符合 HABC 的特点，HABC 临床诊断成立。先证者 TUBB4A c．974G ＞T（p．Trp325Leu）为新生致病性突变，为国际上尚未报道的新突变，扩展了 TUBB4A 的突变谱。明确了 HABC 一家系临床与分子遗传学特征，为准确的遗传咨询和进一步的产前诊断打下了基础。此为国内首次报道 TUBB4A 突变导致 HABC。

Objective To analyze the clinical data and TUBB4A mutation of hypomyelination with atrophy of the basal ganglia and cerebellum (HABC)in a family,thus to provide accurate genetic counseling and prenatal diagno-sis for this family with HABC,and also to provide clinical experience for the diagnosis of HABC in China.Methods The clinical data of the proband and her family members were collected at the Department of Pediatrics,Peking Univer-sity First Hospital,December 201 4,including medical history,physical signs,and brain MRI,biochemical tests and metabolic disease screening.The associated gene of hereditary leukoencephalopathy was screened for the proband and her family members were screened by targeting -high -throughput sequencing technology,and then the genetic varia-tions were verified by Sanger sequencing.With those detection methods,the gene mutation was confirmed,and then ge-netic features were analyzed.Results Clinical features were as follows:nystagmus as the first symptom,and motor and mental retardation,dystonia and ataxia followed.Brain MRI indicated hypomyelination of white matter and atrophy of the basal ganglia and cerebellum.The clinical diagnosis of HABC was established based on the clinical features and brain MRI features above.Genetics features showed that one novel TUBB4A c.974G >T heterozygous missense muta-tion was found from the proband,which caused an amino acid change from the Trp into Leu (p.Trp325Leu).Both of her parents with normal phenotype were of wild -type in this site.Conclusions The proband from this family was diagnosed clinically based on her clinical data.One novel TUBB4Ac.974G > T (p.Trp325Leu)was founded in this study.Therefore,the spectrum of TUBB4A mutation will be expanded.In addition,this study elucidated clinical and genetic characteristics in this family with HABC,which may lay a solid foundation for the accurate genetic counseling and prenatal diagnosis.This study reported the first case of HABC caused by TUBB4A mutation in China.