Cheng Shuangxi, Wang Qingming, Chen Aixin, Zhou Lingfang, Hong Xiaochun, Yuan Haiming
Dongguan Maternal and Child Health Care Hospital, Dongguan, Guangdong 523120, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 May 10;39(5):537-541.
To explore the genotype-phenotype correlation of a case with GM1-gangliosidosis caused by compound heterogenic variants in GLB1.
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.
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.
Our study expands the mutational spectrum of the GLB1 gene and provides genetic counseling for the family.
探讨1例由GLB1基因复合杂合变异导致的GM1神经节苷脂贮积症患者的基因型-表型相关性。
从患者及其父母的外周血样本中提取基因组DNA。对该家系进行了基于三联体的全外显子组测序（WES），并通过Sanger测序验证了疑似突变。
先证者为一名2岁3个月大的中国女孩，表现为精神运动发育迟缓、失语、智力残疾和行为问题。基于三联体的WES在GLB1基因中鉴定出2个变异的复合杂合性：NM_000404.2:c.1343A>T，p.Asp448Val和c.1064A>C，p.Gln355Pro（GRCh37/hg19），分别遗传自母亲和父亲。编码β-半乳糖苷酶的GLB1基因中的纯合或复合杂合致病性变异是导致GM1神经节苷脂贮积症的原因，这是一种常染色体隐性溶酶体贮积症，其特征为不同程度的神经退行性变和骨骼异常。p.Asp448Val变异在医学文献中已被归类为GM1神经节苷脂贮积症的致病突变，因为功能研究表明，与野生型GLB1相比，p.Asp448Val变异在COS-1细胞中的表达未检测到β-半乳糖苷酶活性。p.Gln355Pro变异在文献或数据库中尚未见报道。该变异是高度保守残基（PM1），在基因组聚合数据库或千人基因组计划中均未发现（PM2），并且多种计算机预测工具预测该变异对基因产物具有有害影响（PP3）。接下来，通过荧光法测定患者外周血白细胞的β-半乳糖苷酶活性。结果为0.0 nmol/mg。表明p.Gln355Pro变异也导致β-半乳糖苷酶活性丧失，因此该变异被归类为临床致病变异。
我们的研究扩展了GLB1基因的突变谱，并为该家系提供了遗传咨询。
