Influences of RASopathies on Neuroanatomical Variation in Children

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• RASopathies are genetic disorders caused by mutations in the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway.
• Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are distinct RASopathies associated with increased risks for autism spectrum disorder and attention-deficit/hyperactivity disorder.

Purpose of the Study:

• To investigate the effects of RASopathies (NS and NF1) on human neuroanatomy, focusing on cortical surface area (SA), cortical thickness (CT), and subcortical volumes.
• To compare neuroanatomical differences between children with RASopathies and typically developing children.

Main Methods:

• Structural T1-weighted MRI images were acquired from children with RASopathies (n=91) and age/sex-matched typically developing children (n=74).
• Vertex-based analysis was used for cortical measures (SA and CT).
• Desikan region of interest parcellation was employed for subcortical volume analysis.

Main Results:

• RASopathies demonstrated convergent effects on SA and CT, with increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus.
• RASopathies exhibited divergent effects on subcortical volumes, with syndrome-specific patterns.
• Children with NS showed decreased volumes in striatal and thalamic structures, while children with NF1 displayed increased volumes in the hippocampus, amygdala, and thalamus.

Conclusions:

• RASopathies have both shared and distinct neuroanatomical effects on human neurodevelopment.
• The convergence of cortical SA and CT changes suggests a common impact of Ras/MAPK pathway hyperactivation on the brain.
• Cortical SA and CT measures may serve as objective outcome indicators for targeted therapeutic interventions in RASopathies.