CYP7B1基因突变相关的复杂型遗传性痉挛性截瘫家系的临床特征及遗传学分析  

Clinical characteristics and genetic analysis of CYP7B1 gene mutation-associated complex hereditary spastic paraplegia pedigrees

作　　者：张玉薇 张杰文[2] 娄桂予[1] 张冰[1] 陈玉升[3] 梅文丽[4] 祁娜 雷星星 杨科[1] Zhang Yuwei;Zhang Jiewen;Lou Guiyu;Zhang Bing;Chen Yusheng;Mei Wenli;Qi Na;Lei Xingxing;Yang Ke(Institute of Medical Genetics of Henan Provincial People′s Hospital,Zhengzhou 450003,China;Department of Neurology,Henan Provincial People′s Hospital,Zhengzhou 450003,China;Department of Neurosurgery,Henan Provincial People′s Hospital,Zhengzhou 450003,China;Department of Neurophysiology,Henan Provincial People′s Hospital,Zhengzhou 450003,China)

机构地区：[1]河南省人民医院医学遗传研究所,郑州450003 [2]河南省人民医院神经内科,郑州450003 [3]河南省人民医院神经外科,郑州450003 [4]河南省人民医院神经电生理科,郑州450003

出　　处：《中华神经科杂志》2024年第8期881-889,共9页Chinese Journal of Neurology

摘　　要：目的分析3个在儿童期起病的复杂型遗传性痉挛性截瘫(HSP)5型家系先证者的临床表型和遗传学特征,同时对HSP5型的遗传学诊断方法进行探索,以提高临床对此病的诊断及鉴别诊断能力。方法收集2020年6月至2023年1月就诊于河南省人民医院的3个HSP5型家系的临床资料,对家系中的患者进行全外显子组测序(WES),分析与表型相关的基因变异类型,包括单核苷酸变异(SNV)和小片段插入/缺失变异(INDEL)分析,同时对特定基因的动态突变区域进行分析。结果3个家系中的先证者均为复杂型HSP:家系1先证者临床表现为双下肢无力、尿急、共济失调;家系2先证者表现为智力稍低、双下肢无力、构音障碍,头颅磁共振成像示脑白质病变;家系3先证者表现为双下肢肌无力、痉挛、尿频、共济失调。测序结果显示:先证者1及其弟弟存在CYP7B1基因c.1171G>T(父源)及c.1249C>T(母源)复合杂合变异;先证者2及其妹妹存在CYP7B1基因c.334C>T(父源)及c.259+2T>C(母源)复合杂合变异;先证者3存在CYP7B1基因c.334C>T(父源)及c.1082G>A(母源)复合杂合变异。其中c.1171G>T为未报道过的新变异。基因动态突变分析结果显示,患儿的ATXN1/2/3/6/7/8/12、DRPLA、TBP基因的CAG重复次数均在正常范围内。根据患儿的临床表现及基因检测结果,HSP5型诊断明确。结论本研究中的3个家系均为CYP7B1基因复合杂合变异导致的复杂型HSP5型。WES可同时分析SNV、INDEL和动态突变进而明确相关疾病的诊断,可以作为HSP5型的一种有效的检测方法。Objective To analyze the clinical phenotype and genetic characteristics of probands in 3 pedigrees of complex hereditary spastic paraplegia type 5(HSP5)who developed symptoms during childhood,and the genetic diagnostic methods of HSP5 to improve the diagnosis and differential diagnosis of this disease.Methods The clinical data of 3 HSP5 families admitted to Henan Provincial People′s Hospital from June 2020 to January 2023 were collected.Whole exome sequencing(WES)was performed on the patients to analyze phenotype-related single nucleotide variation(SNV)and small fragment insertion/deletion(INDEL)variation.At the same time,the sequencing data were used to analyze the dynamic mutation regions of specific genes.Results The probands in the 3 families had complex HSP:the proband in family 1 showed weakness of both lower limbs,urgency of urination and ataxia;the proband in family 2 showed slightly lower intelligence,weakness of both lower limbs,dysarthria,and brain magnetic resonance imaging showed white matter lesions;the proband in family 3 showed muscle weakness,spasm,frequent urination and ataxia of both lower limbs.The sequencing results showed that the CYP7B1 gene c.1171G>T(paternal)and c.1249C>T(maternal)compound heterozygous mutations were found in proband 1 and his younger brother.The CYP7B1 gene c.334C>T(paternal)and c.259+2T>C(maternal)compound heterozygous mutations were found in proband 2 and her younger sister.The CYP7B1 gene c.334C>T(paternal)and c.1082G>A(maternal)compound heterozygous mutations were found in proband 3.And c.1171G>T was a new variant that had not been reported before.Dynamic mutation analysis showed that the numbers of CAG repeats of ATXN1/2/3/6/7/8/12,DRPLA,TBP genes were within the normal range.According to the clinical manifestations and genetic examination results of the children in the 3 pedigrees,the diagnosis of HSP5 was clear.Conclusions The 3 families in the study all had complex HSP5 caused by compound heterozygous mutations of the CYP7B1 gene.WES can analyze SNV,INDEL and d

关 键 词：痉挛性截瘫 遗传性 CYP7B1基因 突变 

分 类 号：R725.9[医药卫生—儿科]