一例青少年型异染性脑白质营养不良患者的基因变异分析  

Analysis of genetic variant in a patient with juvenile meterochromic leukodystrophy

作　　者：张肖[1] 李苗苗[1] 马建华[2] 臧玉翠[1] 王敬丽[1] 徐瑛蕾[1] 沈露 刘世国[1] Zhang Xiao;Li Miaomiao;Ma Jianhua;Zang Yucui;Wang Jingli;Xu Yinglei;Shen Lu;Liu Shiguo(Department of Medical Genetics,the Affiliated Hospital of Qingdao University,Qingdao,Shandong 266000,China;Department of Reproductive Medicine,the Affiliated Hospital of Qingdao University,Qingdao,Shandong 266000,China)

机构地区：[1]青岛大学附属医院医学遗传科,山东266000 [2]青岛大学附属医院生殖医学科,山东266000

出　　处：《中华医学遗传学杂志》2022年第10期1093-1098,共6页Chinese Journal of Medical Genetics

基　　金：国家重点研发计划(2016YFC1000306)。

摘　　要：目的分析一例青少年型异染性脑白质营养不良病(metachromatic leukodystrophy,MLD)患儿的芳基硫酸酯酶A(arylsulfatase A,ARSA)基因的变异情况。方法收集先证者的临床资料,采集先证者及其他家系成员的外周静脉血样并提取基因组DNA。通过全外显子组测序确定可疑致病变异后,应用Sanger测序在该家系中进行验证。通过氨基酸多序列比对和蛋白三维模型预测对变异的致病性进行分析。结果患者携带ARSA基因c.257G>A(p.R86Q)和c.467del(p.G156Afs*6)复合杂合变异,其中c.467del(p.G156Afs*6)移码变异为尚未报道的致病变异。氨基酸多序列比对表明c.257G>A(p.R86Q)变异位点在各种属间高度保守。经蛋白三维结构建模分析发现变异体c.467del(p.G156Afs*6)蛋白构象发生变化导致原有功能的丧失。结论本研究发现新的基因变异位点,扩宽了MLD的变异谱,有助于进一步了解基因型与表型之间的关系,加深对于该病的认识。Objective To explore the genetic basis for a child with metachromatic leukodystrophy(MLD).Methods Clinical data of the patient was collected.Genomic DNA was extracted from peripheral blood samples of the child and his family members.Potential variant was screened by whole exome sequencing(WES),and candidate variant was verified by Sanger sequencing.The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product.Results The child was found to harbor compound heterozygous variants c.257G>A(p.R86Q)and c.467del(p.G156Afs*6)of the ARSA gene,among which the c.467del(p.G156Afs*6)frameshift variation was unreported previously.Multiple sequence alignment showed that the site of the c.257G>A(p.R86Q)missense variant is highly conserved.Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein.Conclusion The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.

关 键 词：ARSA基因 异染性脑白质营养不良 全外显子组测序 生物信息学分析 

分 类 号：R742[医药卫生—神经病学与精神病学]