Dose-dependent myelin g-ratio alterations in the white matter of 16p11.2 copy number variations

Abstract

Copy number variations (CNVs) at the 16p11.2 locus are major genetic risk factors for neurodevelopmental conditions and drive reciprocal alterations in cerebral white matter structure and connectivity. However, whether these alterations reflect differences in the axonal or myelin compartments remains unresolved with conventional diffusion MRI. We combined diffusion MRI with magnetization transfer saturation mapping across two ComBat-harmonized cohorts comprising 80 controls, 26 16p11.2 deletion carriers, and 13 duplication carriers. We quantified axonal volume, myelin volume, and aggregate g-ratio of white matter tracts forming the structural connectome. Metrics were evaluated using normative modeling across tract length, resting-state functional networks, and cortical nodes. We additionally examined 29 individuals carrying other neurodevelopmental CNVs. 16p11.2 gene dosage was associated with regional reciprocal differences in tract axonal volume, with greater volume in deletion carriers and lower volume in duplication carriers. In contrast, myelin volume did not differ significantly from controls. This mismatch resulted in pervasive aggregate g-ratio alterations, with higher g-ratios (relatively thinner myelin sheaths) in deletion carriers and lower g-ratios (relatively thicker sheaths) in duplication carriers. Regional g-ratio alterations also extended to other neurodevelopmental CNVs. These findings resolve some of the biological ambiguity underlying white matter alterations in 16p11.2 CNV carriers, implicating the axonal compartment while revealing comparatively stable myelin volume. The disrupted axon-myelin scaling results in connectome-wide g-ratio alterations and may represent a shared microstructural hallmark of genetic neurodevelopmental risk.