Evidence map›Paper›PMID 42297935›Full record

ArticleMolecular psychiatry2026

Evidence supporting the role of GIGYF2 in synapse development and autism.

Bin Yu, Shimeng Zhu, Linhu Xiao, Guodong Chen, Suixin Deng, Ziyang Wang, Ruijia Zhuang, Yongqing Lyu, Senwei Tan, Xiangbin Jia and 31 more

Abstract read
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Article in Molecular psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

41 authors.

Bin Yu *Hunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Shimeng Zhu *Hunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Linhu XiaoInstitute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
Guodong ChenHunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, China.
Suixin DengHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Ziyang WangHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Ruijia ZhuangHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Yongqing LyuHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Senwei TanHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Xiangbin JiaHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Xinyue LiaoFurong Laboratory, Changsha, Hunan, 410078, China.
Yang LiaoHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Xiangyu LiHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Ge ZhangHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Qiumeng ZhangHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Yizheng JiangHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Ting BaiHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Pisheng ZhuHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Lu ShenReproductive Medicine Center, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Kendra HoekzemaDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Franziska SchnabelInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0002-1542-1399
Hilde PeetersCentre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, 3000, Belgium.
Sophie RondeauService de médecine génomique des maladies rares, Necker Hospital, Paris, France.
Marlène RioService de médecine génomique des maladies rares, Necker Hospital, Paris, France.
Giulia BarciaService de médecine génomique des maladies rares, Necker Hospital, Paris, France.
Rachel FisherDepartment of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, 48109-5718, USA.
Mark C HannibalDepartment of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, 48109-5718, USA.
Olivia L KeslerDepartment of Genetics, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
Nathaniel H RobinDepartment of Genetics, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
Isabelle ThiffaultChildren's Mercy Research Institute, Genomic Medicine Center, University of Missouri-Kansas City (UMKC) School of Medicine, Kansas City, MO, 64108, USA.
Vitoria K PaolilloChildren's Mercy Research Institute, Genomic Medicine Center, University of Missouri-Kansas City (UMKC) School of Medicine, Kansas City, MO, 64108, USA.
Jonas HelbigLabor Dr. Fenner und Kollegen, Medical Care Center for Laboratory Medicine and Human Genetics (MVZ), Hamburg, Germany.
Ling YuanHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Zhengmao HuHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.ORCID http://orcid.org/0000-0002-3921-8205
Jiada LiHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.ORCID http://orcid.org/0000-0002-4236-3518
Jieqiong TanHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-8246-4014
Kun XiaHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China. xiakun@sklmg.edu.cn.ORCID http://orcid.org/0000-0001-8090-6002
Hui GuoHunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, MOE Key Lab of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China. guohui2@csu.edu.cn.ORCID http://orcid.org/0000-0002-1570-2545

Funding

Sporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2M
Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R01MH101221National Natural Science Foundation of China (National Science Foundation of China) no. 32271026National Natural Science Foundation of China (National Science Foundation of China) no. 82201706National Natural Science Foundation of China (National Science Foundation of China) no.82330035National Natural Science Foundation of China (National Science Foundation of China) no.82361138573National Natural Science Foundation of China (National Science Foundation of China) no. 82401388National Natural Science Foundation of China (National Science Foundation of China) no. 82402171National Natural Science Foundation of China (National Science Foundation of China) nos. 82222025 and 32271141Natural Science Foundation of Hunan Province (Hunan Provincial Natural Science Foundation) nos. 2023RC1020 and 2023SK2084Natural Science Foundation of Hunan Province (Hunan Provincial Natural Science Foundation) nos. 2024JJ6082Natural Science Foundation of Hunan Province (Hunan Provincial Natural Science Foundation) nos. 2024JJ6545Natural Science Foundation of Hunan Province (Hunan Provincial Natural Science Foundation) nos. 2025JJ20021Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation) no. ZR2022QH215NIMH NIH HHS R01 MH101221
6 · The paper itself

Abstract

Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.

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PMID42297935

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