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  • Systematic Review
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Brain volumes in genetic syndromes associated with mTOR dysregulation: a systematic review and meta-analysis

Molecular Psychiatry volume 30, pages 1676–1688 (2025)Cite this article

Subjects

Abstract

Background/objectives

Dysregulation of molecular pathways associated with mechanistic target of rapamycin (mTOR) and elevated rates of neurodevelopmental disorders are implicated in the genetic syndromes neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Noonan syndrome (NS). Given shared molecular and clinical features, understanding convergent and divergent implications of these syndromes on brain development may offer unique insights into disease mechanisms. While an increasing number of studies have examined brain volumes in these syndromes, the effects of each syndrome on global and subcortical brain volumes are unclear. Therefore, the aim of the current study was to conduct a systematic review and meta-analysis to synthesize existing literature on volumetric brain changes across TSC, FXS, NF1, and NS. Study outcomes were the effect sizes of the genetic syndromes on whole brain, gray and white matter, and subcortical volumes compared to typically developing controls.

Subjects/methods

We performed a series of meta-analyses synthesizing data from 23 studies in NF1, TSC, FXS, and NS (pooled N = 1556) reporting whole brain volume, gray and white matter volumes, and volumes of subcortical structures compared to controls.

Results

Meta-analyses revealed significantly larger whole brain volume, gray and white matter volumes, and subcortical volumes in NF1 compared to controls. FXS was associated with increased whole brain, and gray and white matter volumes relative to controls, but effect sizes were smaller than those seen in NF1. In contrast, studies in NS indicated smaller whole brain and gray matter volumes, and reduced subcortical volumes compared to controls. For individuals with TSC, there were no significant differences in whole brain, gray matter, and white volumes compared to controls. Volumetric effect sizes were not moderated by age, sex, or full-scale IQ.

Conclusions

This meta-analysis revealed that dysregulation of mTOR signaling across pre- and post-natal periods of development can result in convergent and divergent consequences for brain volume among genetic syndromes. Further research employing advanced disease modeling techniques with human pluripotent stem cell-derived in vitro models is needed to further refine our understanding of between and within syndrome variability on early brain development and identify shared molecular mechanisms for the development of pharmaceutical interventions.

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Fig. 1: mTOR pathway.
Fig. 2: Whole brain volume.
Fig. 3: Gray matter volume.
Fig. 4: White matter volume.

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Data availability

Data used of the current study were reported in articles as cited in this paper.

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Acknowledgements

JMP is funded by a Murdoch Children’s Research Institute Clinician-Scientist Fellowship. DRH is supported by a Discovery Early Career Researcher Award (DE160100042). SV is supported by the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), funded by the Novo Nordisk Foundation grant NNF21CC0073719. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Jonathan M. Payne, Kristina M. Haebich, Rebecca Mitchell, Kiymet Bozaoglu, Emma Giliberto, Paul J. Lockhart, Alice Maier, Silvia Velasco, Gareth Ball & Kathryn N. North

  2. Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia

    Jonathan M. Payne, Kristina M. Haebich, Rebecca Mitchell, Kiymet Bozaoglu, Paul J. Lockhart, Silvia Velasco, Gareth Ball & Kathryn N. North

  3. School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia

    Emma Giliberto & Darren R. Hocking

  4. The Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW Melbourne, Melbourne, VIC, Australia

    Silvia Velasco

  5. Institute for Health & Sport, Victoria University, Melbourne, VIC, Australia

    Darren R. Hocking

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Contributions

JMP and KMH had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the analysis. All authors approved the final version before submission. Study concept and design: JMP, DRH. Acquisition, of data: JMP, EG, KMH, RM, AM. Interpretation of data: JMP, KMH, RM, KB, EG, PJL, AM, SV, GB, KNN, DRH. Drafting of manuscript: JMP, EG. Critical revision of the manuscript for important intellectual content: KMH, RM, KB, PJL, AM, SV, GB, KNN, DRH. Statistical analysis: KMH, EG. Study supervision: JMP, DRH. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

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Payne, J.M., Haebich, K.M., Mitchell, R. et al. Brain volumes in genetic syndromes associated with mTOR dysregulation: a systematic review and meta-analysis. Mol Psychiatry 30, 1676–1688 (2025). https://doi.org/10.1038/s41380-024-02863-4

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