摘要目的:探讨一例GM1-神经节苷脂贮积症患儿的基因型与表型的关系。方法:采用全外显子测序(whole-exome sequencing, WES)对患儿家系进行检测，并应用Sanger测序对可疑变异位点进行验证。取患儿外周血白细胞利用荧光法进行β半乳糖苷酶活性分析。结果:先证者为一名2岁3个月女性患儿，临床表现为精神运动发育倒退，语言缺失，智力障碍和行为异常。WES检测到 GLB1基因发生复合杂合错义变异NM_000404.2：c.1343A>T(p.Asp448Val)和c.1064A>C，(p.Gln355Pro)(GRCh37/hg19)，分别遗传于母亲和父亲。 GLB1p.Asp448Val变异未检测出β半乳糖苷酶活性，因此该变异为临床致病性变异。而p.Gln355Pro变异尚无报道，该变异位点位于β半乳糖苷酶具有催化活性的TIM barrel结构域，在正常人群数据库频率为0，多种计算机软件预测有害。先证者外周血白细胞β半乳糖苷酶活性分析结果表明酶残余活性为0，证明p.Gln355Pro变异也会导致β半乳糖苷酶活性丧失，因此该变异被评估为临床致病性变异。 结论:本研究丰富了 GLB1基因变异谱，为家庭遗传咨询提供了指导。

abstractsObjective:To explore the genotype-phenotype correlation of a case with GM1-gangliosidosis caused by compound heterogenic variants in GLB1. Methods:Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Trio-based whole-exome sequencing (WES) was performed for the family and suspected mutation was verified by Sanger sequencing.Results:The proband, a 2-year-3-month old Chinese girl, presented with psychomotor deterioration, absent speech, intellectual disabilities and behavior problem. Trio-based WES has identified compound heterozygosity for 2 variants in the GLB1 gene: NM_000404.2: c.1343A>T, p. Asp448Val and c. 1064A>C, p. Gln355Pro (GRCh37/hg19), which was inherited from the mother and father, respectively. Homozygous or compound heterozygous pathogenic variants in GLB1, encoding β-galactosidase, are responsible for GM1-gangliosidosis, an autosomal recessive lysosomal storage disorder characterized by variable degrees of neurodegeneration and skeletal abnormalities. The p. Asp448Val variant has been classified as pathogenic for GM1 gangliosidosis in medical literatures for the reason that functional studies demonstrated that expression of the p. Asp448Val variant in COS-1 cells resulted in no detectable β-galactosidase activity compared to wild type GLB1. The p. Gln355Pro variant has not been reported in literatures or database. The variant is highly conserved residue (PM1), and was not found in either the Genome Aggregation Database or the 1000 Genomes Project (PM2) and was predicted to have a deleterious effect on the gene product by multiple in silico prediction tools (PP3). Next, the β-galactosidase activity of the patient's peripheral blood leukocytes was determined by fluorescent method. The result was 0.0 nmol/mg. It showed that the p. Gln355Pro variant also resulted in loss of β-galactosidase activity, thus the variant was classified into clinical pathogenic variant. Conclusion:Our study expands the mutational spectrum of the GLB1 gene and provides genetic counseling for the family.