Opposing Brain Differences in 16p11.2 Deletion and Duplication Carriers

Abstract

Deletions and duplications of the recurrent ϳ600 kb chromosomal BP4 -BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N ϭ 25) and duplication (N ϭ 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N ϭ 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion Ͼ control Ͼ duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development.

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…heterozygous deletions and duplications exhibited abnormal brain volumes, with the largest effect detected in the thalamus, and trends in cerebellum and hippocampus (Qureshi et al 2014). Diffusion tension imaging analyses revealed white matter abnormalities in 16p11.2 deletion carriers, especially in the anterior corpus callosum, and bilateral internal and external capsules (Owen et al 2014).…”

“…16p11.2 deletion syndrome presents with a range of mild-to-severe cognitive impairments, with IQ scores averaging 2 SDs lower than controls, and a confirmed diagnosis of autism in 15% of affected individuals (Hanson et al 2010Zufferey et al 2012;Qureshi et al 2014). 16p11.2 deletion carriers are affected in multiple cognitive domains, including verbal and nonverbal IQ, cognitive flexibility, and spatial working memory (Hanson et al 2010Stefansson et al 2014;Moreno-De-Luca et al 2015).…”

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…[2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume. [9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia. 3,[13][14][15][16] Moreover, the BP2-BP3 deletion and reciprocal duplication have mirror effects on BMI and HC, whereas the duplication of this interval, like the deletion, is associated with ASD.…”

The Promise of Multi-Omics and Clinical Data Integration to Identify and Target Personalized Healthcare Approaches in Autism Spectrum Disorders

“…In one study using sMRI (Qureshi et al, 2014), a mirror phenotype of brain volume was observed for individuals with ASD and a copy number variation within the 16p11.2 locus, such that compared to controls, deletion carriers exhibited increases and duplication carriers exhibited decreases in brain size. Other work has associated autism risk genes to structural and functional brain connectivity (e.g., CNTNAP2) (Dennis et al, 2011;Rudie et al, 2012).…”