Zagaynova Valeria A, Nasykhova Yulia A, Tonyan Ziravard N, Danilova Maria M, Dvoynova Natalya M, Lazareva Tatyana E, Ivashchenko Tatyana E, Shabanova Elena S, Krikheli Inna O, Lesik Elena A, Bespalova Olesya N, Kogan Igor Yu, Glotov Andrey S
D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint-Petersburg, Russia.
Front Genet. 2024 Feb 9;15:1344051. doi: 10.3389/fgene.2024.1344051. eCollection 2024.
Ganglioside-monosialic acid (GM1) gangliosidosis (ICD-10: E75.1; OMIM: 230500, 230600, 230650) is a rare autosomal recessive hereditary disease, lysosomal storage disorder caused by mutations in the gene that lead to the absence or insufficiency of β-galactosidase. In this study, we report a case of a Russian family with a history of GM1 gangliosidosis. The family had a child who, from the age of 6 months, experienced a gradual loss of developmental skills, marked by muscle flaccidity, psychomotor retardation, hepatosplenomegaly, and the onset of tonic seizures by the age of 8 months. Funduscopic examination revealed a «cherry red spot» in the macula, which is crucial for the diagnosis of lipid storage disorders. To find the pathogenic variants responsible for these clinical symptoms, the next-generation sequencing approach was used. The analysis revealed two variants in the heterozygous state: a frameshift variant c.699delG (rs1452318343, ClinVar ID 928700) in exon 6 and a missense variant c.809A>C (rs371546950, ClinVar ID 198727) in exon 8 of the gene. The spouses were advised to plan the pregnancy with assisted reproductive technology (ART), followed by preimplantation genetic testing for monogenic disorder (PGT-M) on the embryos. Trophectoderm biopsy was performed on 8 out of 10 resulting embryos at the blastocyst stage. To perform PGT-M, we developed a novel testing system, allowing for direct analysis of disease-causing mutations, as well as haplotype analysis based on the study of polymorphic markers-short tandem repeats (STR), located upstream and downstream of the gene. The results showed that four embryos were heterozygous carriers of pathogenic variants in the gene (#1, 2, 5, 8). Two embryos had a compound heterozygous genotype (#3, 4), while the embryos #7 and 9 did not carry disease-causing alleles of the gene. The embryo #7 without pathogenic variants was transferred after consideration of its morphology and growth rate. Prenatal diagnosis in the first trimester showed the absence of the variants analyzed in the gene in the fetus. The pregnancy resulted in the delivery of a female infant who did not inherit the disease-causing variants in the gene.
神经节苷脂单唾液酸（GM1）神经节苷脂沉积症（国际疾病分类第十版：E75.1；在线人类孟德尔遗传数据库：230500、230600、230650）是一种罕见的常染色体隐性遗传性疾病，是由基因突变导致β-半乳糖苷酶缺乏或不足引起的溶酶体贮积症。在本研究中，我们报告了一个有GM1神经节苷脂沉积症病史的俄罗斯家庭病例。该家庭有一个孩子，从6个月大开始逐渐丧失发育技能，表现为肌肉松弛、精神运动发育迟缓、肝脾肿大，并在8个月大时开始出现强直性癫痫发作。眼底检查发现黄斑区有“樱桃红斑”，这对脂质贮积症的诊断至关重要。为了找到导致这些临床症状的致病变异，采用了下一代测序方法。分析发现两个杂合状态的变异：外显子6中的移码变异c.699delG（rs1452318343，临床变量标识符928700）和该基因外显子8中的错义变异c.809A>C（rs371546950，临床变量标识符198727）。建议这对配偶通过辅助生殖技术（ART）计划怀孕，随后对胚胎进行单基因疾病植入前基因检测（PGT-M）。在囊胚期对10个胚胎中的8个进行了滋养外胚层活检。为了进行PGT-M，我们开发了一种新型检测系统，能够直接分析致病突变，并基于对位于该基因上游和下游的多态性标记——短串联重复序列（STR）的研究进行单倍型分析。结果显示，4个胚胎是该基因致病变异的杂合携带者（#1、2、5、8）。2个胚胎具有复合杂合基因型（#3、4），而胚胎#7和9不携带该基因的致病等位基因。在考虑胚胎#7的形态和生长速度后，将没有致病变异的胚胎#7进行了移植。孕早期的产前诊断显示胎儿中未检测到该基因中分析的变异。此次怀孕产下一名女婴，她没有遗传该基因的致病变异。
