知的障害と言語発達遅延を有する患者で同定されたSTAG1遺伝子変異の解析

Autosomal dominant intellectual developmental disorder (type 47) (OMIM #617635) is associated with heterozygous variants in the STAG1 gene (OMIM*604358). The main clinical manifestations include intellectual disability, delayed language development, abnormal facial features, epilepsy, etc. In this study, we performed the whole-exome sequencing (WES) on a 3-year-old child diagnosed with psychomotor developmental delay, and verified candidate gene variants by Sanger sequencing. We constructed a mutant plasmid expression vector and subsequently transfected it into HEK293T cells to preliminarily investigate the pathogenic mechanism of the identified variant. Additionally, we conducted a comprehensive review of previously published literature to systematically summarize the associated clinical phenotypes. WES revealed that the patient harbored the c.500dup (p.Gly168TrpfsTer13) of the STAG1 gene, and it was a de novo variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as a pathogenic variant (PVS1+PM2_Supporting+PS2_Supporting). In vitro cellular function studies have demonstrated that this variant resulted in a substantial decrease in the expression of mutant mRNA, thereby impairing the production of functional STAG1 protein. Clinical phenotypes associated with STAG1 gene variants display considerable variability. This study suggests that the pathogenic mechanism of STAG1 gene variants may be linked to haploinsufficiency of the gene.