SACS基因变异所致Charlevoix-Saguenay型痉挛性共济失调患儿1例的遗传学分析

Genetic analysis of a child with Charlevoix-Saguenay spastic ataxia due to variant ofSACS gene

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中文摘要：目的探讨1例常染色体隐性遗传Charlevoix-Saguenay型痉挛性共济失调(ARSACS)患儿的临床及SACS基因变异特征。方法分析2021年4月30日收治于四川大学华西第二医院的1例ARSACS患儿的临床资料，对患儿及其父母进行全外显子组测序(WES)以及Sanger测序家系验证。依照美国医学遗传学与基因组学学会(ACMG)相关指南，利用生物信息学软件对候选变异进行致病性评级。结果患儿为3岁3月龄女性，因"行走不稳1+年"就诊，主要表现为进行性加重的步态不稳，右侧肢体肌张力增高，下肢周围神经病变和视网膜神经纤维层增厚。WES检测提示其携带母源性SACS基因第1 ~ 10外显子杂合缺失，同时第10外显子区存在c.3328dupA新发杂合变异。根据ACMG相关指南，exon(1-10)del被评级为可能致病性变异(PVS1+PM2_Supporting)，c.3328dupA被评级为致病性变异(PVS1_Strong+PS2 +PM2_Supporting)，二者均未被正常人群数据库收录。结论患者SACS基因第10外显子c.3328dupA杂合变异以及第1 ~ 10外显子杂合缺失可能是患儿的遗传学病因。 Objective To explore the clinical feature and genetic variant of a child with autosomal recessive Charlevoix-Saguenay type spastic ataxia (ARSACS). Methods Clinical data of a child who was admitted to the West China Second Hospital of Sichuan University on April 30, 2021 was collected. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results The child, a 3-year-and-3-month-old female, had a complain of "walking instability for over a year" . Physical and laboratory examination revealed progressive and aggravated gait instability, increased muscle tone of the right limbs, peripheral neuropathy of the lower limbs, and thickening of retinal nerve fiber layer. The results of WES revealed that she has harbored a maternally derived heterozygous deletion of exons 1 to 10 of the SACS gene, in addition with a de novo heterozygous c. 3328dupA variant in exon 10 of the SACS gene. Based on the ACMG guidelines, the exons 1-10 deletion was rated as likely pathogenic (PVS1+ PM2_Supporting), and the c. 3328dupA was rated as a pathogenic variant(PVS1_Strong+ PS2+ PM2_Supporting). Neither variant was recorded in the human population databases. Conclusion The c. 3328dupA variant and the deletion of exons 1-10 of the SACS gene probably underlay the ARSACS in this patient.

外文摘要：Objective To explore the clinical feature and genetic variant of a child with autosomal recessive Charlevoix-Saguenay type spastic ataxia (ARSACS). Methods Clinical data of a child who was admitted to the West China Second Hospital of Sichuan University on April 30, 2021 was collected. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results The child, a 3-year-and-3-month-old female, had a complain of "walking instability for over a year" . Physical and laboratory examination revealed progressive and aggravated gait instability, increased muscle tone of the right limbs, peripheral neuropathy of the lower limbs, and thickening of retinal nerve fiber layer. The results of WES revealed that she has harbored a maternally derived heterozygous deletion of exons 1 to 10 of the SACS gene, in addition with a de novo heterozygous c. 3328dupA variant in exon 10 of the SACS gene. Based on the ACMG guidelines, the exons 1-10 deletion was rated as likely pathogenic (PVS1+ PM2_Supporting), and the c. 3328dupA was rated as a pathogenic variant(PVS1_Strong+ PS2+ PM2_Supporting). Neither variant was recorded in the human population databases. Conclusion The c. 3328dupA variant and the deletion of exons 1-10 of the SACS gene probably underlay the ARSACS in this patient.

外文关键词：

AtaxiaAutosomal recessive inheritanceSACS geneWhole exome sequencingPreschool child

作者：

罗欢、陈小璐、饶雪逸、沈亚君、刘金凤、杨作臻、甘靖、许芯、李岭

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作者单位：

1四川大学华西第二医院儿科　出生缺陷与相关妇儿疾病教育部重点实验室　发育与妇儿疾病四川省重点实验室，成都　610041

2赛福解码（北京）基因科技有限公司，北京　100176

关键词：

共济失调常染色体隐性遗传 SACS基因全外显子组测序学龄前儿童

基金：

国家自然科学基金四川省科技计划四川大学华西第二医院科研项目四川大学华西第二医院科研项目四川大学研究生教育教学改革研究项目四川省卫生健康委普及应用项目

项目编号：

820716862021YFS0093KL115KL072GSSCU202115621PJ049

出版年：

2023

DOI：

10.3760/cma.j.cn511374-20220724-00489

中华医学遗传学杂志

中华医学会

中华医学遗传学杂志

CSTPCDCSCD

影响因子：0.562

ISSN：1003-9406

年,卷(期)：2023.40(5)

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