Reciprocal 16p11.2 Microduplication and Microdeletion Carriers Show Opposing Structural Brain Changes, and Differential Effects on Cortical Thickness Vs Surface Area

Background: Over 100 monogenic disorders and over 40 recurrent copy-number variations (CNVs) have been implicated in ASD. In face of this genetic heterogeneity, the Simons VIP Consortium took a genetics-first approach to studying ASD and neurodevelopmental disorder by recruiting a large number of subjects with a recurrent ~600 kb (BP4-BP5) 16p11.2 microdeletion or microduplication. In ASD this CNV occurs at a frequency of 0.76%. Notably, mirror phenotypes occur with deletion carriers  with larger head sizes and obesity, whereas duplication carriers can have smaller head sizes and low body mass index. Differences in head circumference in 16p11.2 carriers are of particular relevance to autism, since macrocephaly is more common in autism. This may suggest that early brain overgrowth is fundamental to the pathobiology of some forms of autism.

Objectives: 16p11.2 may serve as a model to examine the early overgrowth hypothesis in autism. To date, there has been no study evaluating brain structure of 16p11.2 microdeletions and microduplications. It is unknown whether the change in head size is due to a global increase in cortical and/or subcortical volumes or whether there is differential growth in brain structures. Examination of structural morphometry may provide insight into the mechanism for aberrant neurocognitive development in 16p11.2 

Methods: Twenty-five pediatric deletion carriers and 43 pediatric controls (ages 8 to 17), as well as 19 adult duplication carriers and 43 adult controls (ages 19 to 63) were recruited from the Simons VIP study. All structural MR imaging was performed at UCSF and CHOP and then analyzed at Harvard using FreeSurfer version 4.5.0 software package.

Results: Cortical and subcortical estimates show opposing effects between duplication and deletion carriers. Deletion carriers have increased volume compared to control subjects, while duplication carriers show decreased volume. This difference was observed in intracranial volume, brain volume, cortical gray matter volume, and cortical white matter volume (p < 0.001). Cerebellar volume and thalamic volume were significantly different (p < 0.05), and hippocampus/amygdale volumes approached significant difference (p < 0.06). Allometric scaling of cortical gray matter versus intracranial volume alleviates concern that age-dependent effects may be confounded with the effect of CNV, thus confirming the reciprocal nature of the brain volumes in deletion vs. duplication carriers. Further analysis showed strikingly differential effects on the components of gray matter volume: surface area was significantly different between cases and controls (p < 0.005), whereas no difference was found on estimates of cortical thickness (p > 0.24). 

Conclusions: The effect from 16p11.2 is dependent on the dosage of the CNV: 1 copy (deletion), 2 copies (controls), or three copies (duplication). This CNV has highly significant effects on brain volume, and 16p11.2 differentially affects cortical surface area but not the thickness of the cortical ribbon. This suggests that 16p11.2 may influence an early stage of embryonic brain development.