Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy

Yuda Wei; Kai Liu; Changrui Mi; Jing Yu; Ruopeng Sun; Shengxing Miao; Haiqi Li; Huili Xue; Xiaxia Liu; Yanyan Hu; Yongzhen Qi; Jie Zhang; Lili Tong; Chen Zhao; Liangqian Jiang; Juan Teng; Xingzhu Geng; Chengcheng Gai; Hongyan Xu; Lin Li; Fengyuan Che; Chunhai Gao; Xiangyu Zhao

doi:10.1016/j.gim.2025.101668

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy

Genet Med. 2026 Mar;28(3):101668. doi: 10.1016/j.gim.2025.101668. Epub 2025 Dec 17.

Authors

Yuda Wei¹, Kai Liu¹, Changrui Mi², Jing Yu³, Ruopeng Sun⁴, Shengxing Miao⁵, Haiqi Li⁶, Huili Xue⁷, Xiaxia Liu¹, Yanyan Hu², Yongzhen Qi⁸, Jie Zhang⁹, Lili Tong⁴, Chen Zhao¹⁰, Liangqian Jiang¹, Juan Teng¹, Xingzhu Geng¹, Chengcheng Gai¹, Hongyan Xu¹, Lin Li¹, Fengyuan Che¹¹, Chunhai Gao¹², Xiangyu Zhao¹³

Affiliations

¹ Department of Laboratory Medicine, Key Laboratory for Laboratory Medicine of Linyi City, Shandong Provincial Medicine and Health Key Laboratory for Precise Diagnosis of Hereditary Rare Diseases, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China; Department of Medical Genetics, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China.
² Department of Pediatrics, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China.
³ Department of Neurology, Children's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hospital of Beijing Children's Hospital, Urumqi, Xinjiang, China.
⁴ Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
⁵ Rehabilitation Medicine Department, Jiangxi Children's Hospital, Nanchang, Jiangxi, China.
⁶ Department of Child Health Care, Children's Hospital of Chongqing Medical University, Chongqing, China.
⁷ Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital, Fujian Medical University, Fuzhou, Fujian, China.
⁸ Department of Laboratory Medicine, Key Laboratory for Laboratory Medicine of Linyi City, Shandong Provincial Medicine and Health Key Laboratory for Precise Diagnosis of Hereditary Rare Diseases, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China; Department of Medical Genetics, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China; School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, China.
⁹ Department of Imaging, Zhengshan Street Health Center, Linyi, Shandong, China.
¹⁰ Department of Neurology, Weifang People's Hospital, Shandong Second Medical University, Weifang, Shandong, China.
¹¹ Central Laboratory, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China; Department of Neurology, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China. Electronic address: che1971@126.com.
¹² Department of Laboratory Medicine, Key Laboratory for Laboratory Medicine of Linyi City, Shandong Provincial Medicine and Health Key Laboratory for Precise Diagnosis of Hereditary Rare Diseases, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China. Electronic address: gchunhai@126.com.
¹³ Department of Laboratory Medicine, Key Laboratory for Laboratory Medicine of Linyi City, Shandong Provincial Medicine and Health Key Laboratory for Precise Diagnosis of Hereditary Rare Diseases, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China; Department of Medical Genetics, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong, China. Electronic address: xiangyuzhao@126.com.

PMID: 41420488
DOI: 10.1016/j.gim.2025.101668

Abstract

Purpose: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease.

Methods: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system.

Results: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling.

Conclusion: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Keywords: Autism; Epilepsy; GSPT2 gene; Intellectual disability; Language impairment.

MeSH terms

Adolescent
Adult
Autistic Disorder* / genetics
Child
Child, Preschool
Epilepsy* / genetics
Female
Genes, X-Linked
Genetic Association Studies
Genetic Diseases, X-Linked* / genetics
Humans
Intellectual Disability* / genetics
Language Development Disorders / genetics
Male
Neurodevelopmental Disorders* / genetics
Pedigree
Phenotype