An Allometric Approach to Fine-Mapping Subcortical Volume Alterations in RASopathies

Structural neuroimaging in youth with RASopathies has shown alterations in total brain volume (TBV) and subcortical structures. However, whether these subcortical differences scale proportionately with TBV or follow nonlinear allometric relationships remains unclear, limiting accurate interpretation of neuroanatomical findings and their relevance to cognition. Using an allometric framework, this study aimed to determine whether (1) subcortical volumes exhibit deviations from normative scaling in RASopathies and (2) methods used to account for TBV influence the detection of subcortical volume alterations. We examined youth with RASopathies (N=133), including Neurofibromatosis Type-1 (NF1, N=27), Noonan Syndrome (NS, N=100; PTPN11: 72, SOS1: 22, RAF1: 6), and Noonan Syndrome with Multiple Lentigines (NSML, N=5), compared to 80 age- and sex-matched controls. Subcortical volumes were analyzed using an allometric framework, compared with linear TBV correction methods (normalization and covariation), and explored in sex-stratified analyses. Allometric analyses revealed deviations from normative scaling in the thalamus for NF1; the caudate, putamen, ventral striatum, and pallidum for PTPN11; and the ventral striatum for SOS1 No significant deviations were observed for NSML or RAF1 Exploratory sex-stratified analyses suggested similar directional scaling patterns across sexes, with greater deviations in females, although subgroup sizes were small. Comparisons across correction methods demonstrated that linear approaches may overestimate regional differences, whereas thalamic alterations in NF1 and striatal alterations in PTPN11 were consistent across methods, suggesting robust, region-specific genetic effects beyond scaling. These findings highlight genotype-specific deviations from normative allometric scaling and underscore the importance of nonlinear scaling frameworks to accurately characterize neuroanatomical differences in RASopathies.Significance Statement Neurofibromatosis Type-1 and Noonan spectrum disorders are associated with atypical brain size, yet most neuroimaging studies rely on linear correction methods that assume proportional brain scaling. Regional brain allometry poses an important but underappreciated methodological challenge for accurately characterizing neuroanatomical differences in these conditions. Here, we apply a normative allometric framework that reveals gene- and sex-specific deviations in subcortical scaling that are potentially overestimated by linear correction approaches. These findings refine the interpretation of brain structure differences in RASopathies and demonstrate the need to account for nonlinear scaling in neurodevelopmental research. Incorporating allometric approaches will improve the biological specificity of neuroimaging markers and inform future efforts toward personalized assessment and intervention.