Subcortical shape alterations in children with Noonan syndrome spectrum: insights into genotype–phenotype associations

Noonan syndrome is the most common RASopathy and is associated with high rates of neurodevelopmental disorders. Prior neuroimaging studies in children with Noonan syndrome have identified structural effects on subcortical regions, though most focus on volumetric differences, overlooking finer morphological changes. These studies also tend to examine common genetic variants, excluding rarer forms within the Noonan syndrome spectrum. Shape analysis offers a sensitive approach to detecting subtle alterations, and when applied across variants, may reveal distinct neuroanatomical signatures. We acquired anatomical magnetic resonance imaging scans from 104 children with Noonan syndrome spectrum (ages 5 to 17, mean = 10.0) and 80 age- and sex-matched typically developing children (ages 4 to 16, mean = 9.54). Our comprehensive analysis examined local thickness and surface dilation/contraction (Jacobian), including genetic variant-specific analyses. Noonan syndrome spectrum showed widespread subcortical alterations beyond volume reduction, including thinning and surface contraction in the putamen, pallidum, thalamus, and caudate, and expansion in the accumbens. Distinct regional effects were found for PTPN11, SOS1, and other Noonan syndrome spectrum-associated variants. These findings confirm subcortical volume reductions in several regions and highlight complex, region-specific shape alterations. Importantly, neuroanatomical patterns varied across genetic variants, suggesting distinct mechanisms of brain development. Understanding these variant-specific structural profiles may provide insights into genotype-based approaches and inform future precision medicine strategies.