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<p>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 <i>GIGYF2</i> 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 <i>GIGYF2</i>. Clinical characterization of 16 probands with <i>GIGYF2</i> variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a <i>Gigyf2</i> cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, <i>Gigyf2</i> 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 <i>Nrp2</i>. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as <i>Nrp2</i> knockdown rescued synaptic defects in <i>Gigyf2</i> KO neurons. These findings define a novel ASD subtype associated with <i>GIGYF2</i> variants and establish <i>GIGYF2</i> as a key regulator of synaptic development and function, implicating <i>GIGYF2</i> dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for <i>GIGYF2</i>-related ASD subtype.</p><p></p>

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Evidence supporting the role of GIGYF2 in synapse development and autism

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • Bin Yu,
  • Shimeng Zhu,
  • Linhu Xiao,
  • Guodong Chen,
  • Suixin Deng,
  • Ziyang Wang,
  • Ruijia Zhuang,
  • Yongqing Lyu,
  • Senwei Tan,
  • Xiangbin Jia,
  • Xinyue Liao,
  • Yang Liao,
  • Xiangyu Li,
  • Ge Zhang,
  • Qiumeng Zhang,
  • Yizheng Jiang,
  • Ting Bai,
  • Pisheng Zhu,
  • Lu Shen,
  • Kendra Hoekzema,
  • Konrad Platzer,
  • Franziska Schnabel,
  • Rami Abou Jamra,
  • Hilde Peeters,
  • Sophie Rondeau,
  • Marlène Rio,
  • Giulia Barcia,
  • Rachel Fisher,
  • Mark C. Hannibal,
  • Olivia L. Kesler,
  • Nathaniel H. Robin,
  • Isabelle Thiffault,
  • Vitoria K. Paolillo,
  • Jonas Helbig,
  • Ling Yuan,
  • Zhengmao Hu,
  • Jiada Li,
  • Jieqiong Tan,
  • Evan E. Eichler,
  • Kun Xia,
  • Hui Guo

摘要

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.