Opposing brain differences in 16p11.2 deletion and duplication carriers.

Area of Science:

• Neurogenetics
• Developmental Neuroscience
• Human Genetics

Background:

• Recurrent deletions and duplications of the 16p11.2 chromosomal region are linked to diverse neurodevelopmental outcomes, including autism spectrum disorder.
• Opposing effects on head size (enlargement with deletion, reduction with duplication) suggest a role for this copy number variant (CNV) in brain pathogenesis.

Purpose of the Study:

• To investigate the impact of 16p11.2 deletions and duplications on human brain structure.
• To compare brain morphology in carriers of these CNVs with age-matched controls.

Main Methods:

• Analysis of brain structure using neuroimaging in clinically ascertained individuals with 16p11.2 deletions (N=25) and duplications (N=17).
• Comparison with age-matched control groups (N=29 and N=33, respectively).
• Detailed analysis of global, compartmental, subcortical, cerebellar, and cortical brain measures.

Main Results:

• Deletion carriers exhibited increased brain size, while duplication carriers showed reduced brain size across multiple measures.
• Effects were pervasive, impacting intracranial volume, gray and white matter, subcortical structures, and the cerebellum, with the thalamus showing the largest quantitative effect.
• Cortical surface area demonstrated a dose-dependent effect (deletion > control > duplication), whereas cortical thickness was less affected.

Conclusions:

• The 16p11.2 CNV exerts opposing influences on brain development, leading to significant alterations in brain size and structure.
• These findings suggest that the CNV impacts early embryonic brain development, potentially through mechanisms affecting cell proliferation or migration.
• The dose-dependent effect on cortical surface area highlights a critical developmental process influenced by this genetic variation.