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Syndrome specific neuroanatomical phenotypes in girls with Turner and Noonan Syndromes

  • Monica Siqueiros Sanchez
    Correspondence
    Corresponding author: Monica Siqueiros Sanchez –
    Affiliations
    Brain Imaging, Development and Genetics (BRIDGE) Lab, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
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  • Bhavana Rai
    Affiliations
    Brain Imaging, Development and Genetics (BRIDGE) Lab, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
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  • Samir Chowdhury
    Affiliations
    Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Brain Dynamics Lab, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
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  • Allan L. Reiss
    Affiliations
    Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Departments of Radiology and Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
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  • Tamar Green
    Affiliations
    Brain Imaging, Development and Genetics (BRIDGE) Lab, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
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Published:September 06, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.08.012

      Abstract

      Background

      Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X-chromosome absence, whereas NS results from genetic mutations activating the Ras mitogen-activated protein kinase (RAS-MAPK) signaling pathway. Previous neuroimaging studies in TS and NS have shown neuroanatomical variations relative to typically developing (TD) individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes.

      Methods

      In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 TD girls, all 5–12 years of age, using univariate and multivariate data-driven analyses.

      Results

      We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. TS was associated with smaller whole-brain cortical surface area (SA) (p=<0.0001) whereas NS was associated with smaller whole-brain cortical thickness (CT) (p=.013) relative to TD. TS was associated with larger subcortical volumes (left amygdala, p=0.002; right hippocampus, p=0.002) whereas NS was associated with smaller subcortical volumes (bilateral caudate, p 0.003; putamen, p<0.001; pallidum, p<0.001; right hippocampus, p=0.015). Multivariate analyses also showed diverging brain phenotypes in terms of SA and CT, with SA outperforming CT at group separation.

      Conclusion

      TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetics etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes.

      Key words

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