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Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay

Molecular Psychiatry volume 30, pages 1952–1965 (2025)Cite this article

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Abstract

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

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Fig. 1: Enrichment analyses of intronic DNVs adjacent to canonical splicing sites (CSS) in ASD cohorts compared to unaffected siblings.
Fig. 2: Prioritization of ASD-risk genes.
Fig. 3: Schematic representation of GSK3B disruptive or de novo missense variants.
Fig. 4: The exogenous expression of GSK3B wildtype, LGD, and missense variants identified from affected individuals in HEK293T cell lines.
Fig. 5: Cell-type-specific expression of GSK3B in the developing human brain.
Fig. 6: GSK3B disruption interferes with dendrite arborization and spine maturity.

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Data availability

The ES and GS data used in this study are available from the following resources. The VCF (Variant Call Format) files for SPARK ES generated by Deepvariant and GS data generated by GATK and SPARK phenotype data used in this study are available through SFARI and available to approved researchers at SFARI Base (https://base.sfari.org/) accession nos. SFARI_SPARK_ES_1, SFARI_ SPARK_ES_2, SFARI_SPARK_ES_3, SFARI_SPARK_ES_4, SFARI_SPARK_GS_1, SFARI_SPARK_GS_2, SFARI_SPARK_GS_3 and SFARI_SPARK_GS_4. All GATK VCF files for SSC GS data and SSC phenotype data are available by request from SFARI Base accession no. SFARI_SSC_GS.

Code availability

All software used in this study is publicly available. The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to the families involved in this study. We thank all of the families in SPARK, the SPARK clinical sites, and the SPARK staff. We thank all of the families at the participating SSC sites, as well as the principal investigators A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Ko- chel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman. We appreciate obtaining access to the phenotypic and genetic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study (https://www.sfari.org/resource/simons-simplex-collection/) and the SPARK population dataset described in this study (https://www.sfari.org/resource/spark/) by applying at https://base.sfari.org. We thank Hartmut Engels for coordinating data collection and assistance.

Funding

This work was partially supported by the High-Performance Computing Center of Central South University. This work was supported in part by the Bioinformatics Center, Xiangya Hospital, Central South University. Funding: This study was supported by STI 2030-Major Project (no. 2021ZD0201704 to HG); National Natural Science Foundation of China (nos. 82222025 and 81871079 to HG; nos. 82130043, 82330035 and 82361138573 to KX); National Key Research and Development Program of China (no. 2021YFA0805200 to ZH and JT), Hunan Provincial grants (nos. 2023RC1020 and 2023SK2084 to HG; nos. 2021SK1010, 2021SK1010 and 2023SK2114 to KX; no. 2019JJ40408 to SZ), Jiangxi Province Key Research and Development Project (no. 20232BBG70023), and the France Genomic Medicine Plan 2025 (SeqOIA).

Author information

Author notes

  1. These authors contributed equally: Senwei Tan, Qiumeng Zhang.

Authors and Affiliations

  1. Center for Medical Genetics & MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China

    Senwei Tan, Qiumeng Zhang, Rui Zhan, Si Luo, Yaoling Han, Bin Yu, Shimin Zhou, Faxiang Li, Zhengmao Hu, Jieqiong Tan, Kun Xia & Hui Guo

  2. Department of Genetics, Nemours Children’s Hospital, Wilmington, DE, USA

    Candace Muss

  3. Service de Médecine Génomique des maladies rares, AP-HP, Hôpital Necker; Université Paris Cité, Inserm, Institut Imagine; and Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France

    Veronique Pingault & Andrée Delahaye

  4. Centre de Référence «Surdités Génétiques», Fédération de Génétique; Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France

    Sandrine Marlin

  5. Laboratory of Embryology and Genetics of Malformations, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France

    Sandrine Marlin

  6. Institute of Human Genetics, School of Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany

    Sophia Peters, Claudia Perne & Martina Kreiß

  7. Center for Genomic Medicine, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain

    Nino Spataro & Juan Pablo Trujillo-Quintero

  8. Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    Caroline Racine & Frederic Tran-Mau-Them

  9. Division of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children’s Hospital, Providence, RI, USA

    Chanika Phornphutkul

  10. Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA

    Aaron D. Besterman

  11. Rady Children’s Hospital, San Diego, CA, USA

    Aaron D. Besterman

  12. Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

    Aaron D. Besterman

  13. Departments of Human Genetics, Pediatrics and Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Julian Martinez

  14. Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Xiuxia Wang & Xiaoyu Tian

  15. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Harvard University, Boston, MA, USA

    Siddharth Srivastava & David K. Urion

  16. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Jill A. Madden

  17. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA

    Jill A. Madden

  18. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Virginia Commonwealth, Richmond, VA, USA

    Hind Al Saif

  19. GeneDx, Gaithersburg, MD, USA

    Michelle M. Morrow & Amber Begtrup

  20. Departments of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China

    Xing Li

  21. Division of Genetics, Genomics and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, USA

    Sarah Jurgensmeyer & Peter Leahy

  22. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, USA

    Sarah Jurgensmeyer & Peter Leahy

  23. MOE Key Lab of Rare Pediatric Diseases, School of Basic Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, China

    Kun Xia

  24. Furong Laboratory, Changsha, Hunan, China

    Kun Xia & Hui Guo

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  1. Senwei Tan
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  2. Qiumeng Zhang
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Contributions

HG, KX, ST, and QZ designed and conceived this study. ST and SL analyzed and interpreted the genomic data. QZ, RZ, YH, BY, and SZ designed and conducted the experiments and analyzed the data. FL, ZH, and JT helped with data interpretation. HG and KX supervised the work. ST, QZ, HG, and KX wrote and revised the manuscript. Other authors including CM, VP, SM, AD, SP, CP, MK, NS, JPT, CR, FT, CP, ADB, JM, XW, XT, SS, DU, JAM, HAS, MMM, AB, XL, SJ and PL contributed and interpreted the genetic and clinical data recruited from an international collaborative network. All authors commented on the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Kun Xia or Hui Guo.

Ethics declarations

Competing interests

AB and MMM are employees of GeneDx, Inc. All of the remaining authors declare no conflict of interest.

Ethics approval and consent to participate

We strictly follow the Guidelines for Clinical Laboratory Biosafety. All of the experimental procedures involving animals were conducted in accordance with the Institutional Animal Care guidelines of Central South University. All cell lines were verified for authenticity. All patient consents were obtained from study participants or their parents or legal guardians, in line with local institutional review board (IRB) requirements at the time of collection. The IRB of Central South University approved this study (Registration number: IRB #2022-1-3).

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Tan, S., Zhang, Q., Zhan, R. et al. Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay. Mol Psychiatry 30, 1952–1965 (2025). https://doi.org/10.1038/s41380-024-02806-z

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