ASAH1基因变异所致Farber病1例胎儿的遗传学分析  

Genetic analysis of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant

作　　者：刘颖文 闫露露 张玉鑫 韩春晓 李海波 Liu Yingwen;Yan Lulu;Zhang Yuxin;Han Chunxiao;Li Haibo(Department of Integrated Birth Defect Control,Women and Children′s Hospital of Ningbo University,Ningbo,Zhejiang 315000,China)

机构地区：[1]宁波大学附属妇女儿童医院出生缺陷综合防治中心,宁波315000

出　　处：《中华医学遗传学杂志》2025年第2期232-237,共6页Chinese Journal of Medical Genetics

基　　金：宁波市医疗卫生高端团队项目(2022020405);宁波市重点技术研发项目(2023Z178);宁波市社会公益项目(2022S035);宁波市科创甬江2035项目(2024Z221)。

摘　　要：目的探讨1例ASAH1基因变异所致Farber病胎儿的临床特点和基因变异。方法选取2024年8月在宁波大学附属妇女儿童医院就诊的1例ASAH1基因变异所致Farber病胎儿为研究对象。收集胎儿临床资料,对胎儿引产组织样本及其父母外周血样本进行全外显子组测序(WES),对候选变异进行Sanger测序验证与生物信息学分析。本研究已通过本院医学伦理委员会审查(批准号:EC2020-048)。结果产前胎儿超声发现本例胎儿全身水肿、心包积液、右侧胸腔积液、肠管回声增强。WES检测发现本例胎儿ASAH1基因第2外显子发生c.101C>A(p.Ser34Ter)纯合无义变异,Sanger测序证实其父母均携带ASAH1基因c.101C>A(p.Ser34Ter)杂合无义变异,该变异尚未被HGMD、ClinVar、1000 Genomes、ExAC、dbSNP及gnomAD等数据库收录。根据美国医学遗传学与基因组学学会(ACMG)《遗传变异分类标准与指南》,该变异被评为致病性(PM2_(S)upporting+PVS1+PM3_(S)upporting)。AlphaFold3模型蛋白结构预测显示,ASAH1基因c.101C>A变异使得其编码蛋白终止密码子提前出现,进而导致ASAH1蛋白仅N端存在小部分α螺旋结构,核心结构域α螺旋结构完全丧失,可能导致该蛋白功能丧失。结论ASAH1基因c.101C>A(p.Ser34Ter)变异导致的Farber病可能是本研究胎儿全身水肿的遗传学病因。c.101C>A(p.Ser34Ter)变异的检出丰富了Farber病的变异谱。ObjectiveTo explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant.MethodsA fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children′s Hospital of Ningbo University in August 2024 was selected as the subject.Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing(WES).Sanger sequencing validation and bioinformatics analysis were performed on candidate variants.This study was approved by Women and Children′s Hospital of Ningbo University(Ethics No.EC2020-048).ResultsGeneralized skin oedema,pericardial effusion,right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound.WES revealed that the fetus has harbored a homozygous c.101C>A(p.Ser34Ter)variation in exon 2 of the ASAH1 gene.Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c.101C>A(p.Ser34Ter)in ASAH1 gene,which has not been included in databases such as HGMD,ClinVar,1000 Genomes,ExAC,dbSNP,and gnomAD.Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics(ACMG),the variant was predicted to be pathogenic(PM2_Supporting+PVS1+PM3_Supporting).The AlphaFold3 model protein structure prediction reveals that the c.101C>A variant caused the premature appearance of a termination codon,resulting in only a small partialα-helix structure in the N-terminal of the encoded ASAH1 protein,with the complete loss of theα-helix structure in the core domain,which might lead to the loss of function of this protein.ConclusionThe c.101C>A(p.Ser34Ter)variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus.The newly discovered c.101C>A(p.Ser34Ter)variant has enriched the mutational spectrum of Farber lipogranulomatosis.

关 键 词：Farber脂肪肉芽肿病 ASAH1基因 水肿胎儿 全外显子组测序 酸性神经酰胺酶 

分 类 号：R714.5[医药卫生—妇产科学]