Polygenicity in a box: Copy number variants, neural circuit development, and neurodevelopmental disorders

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Clinically defined neurodevelopmental disorders (cd-NDDs), such as Autistic Spectrum Disorder (ASD) and Schizophrenia (Scz), are characterized by complex polygenic inheritance.
• The polygenic nature of cd-NDDs, involving numerous risk genes in various combinations, poses a challenge in identifying core pathogenic mechanisms.

Purpose of the Study:

• To investigate whether core pathogenic mechanisms of cd-NDDs can be identified despite genomic complexity.
• To explore Copy Number Variants (CNVs) as a distinct class of polygenic mutations for defining cd-NDD pathology.

Main Methods:

• Utilizing engineered animal and human stem cell models with CNVs orthologous to those conferring cd-NDD risk.
• Analyzing how altered gene function due to CNVs impacts the development of neural circuits.

Main Results:

• Demonstrated that CNVs provide a unique opportunity to study cd-NDD pathology.
• Showcased how altered function of multiple genes leads to developmental 'stumbles' in neural circuit formation.

Conclusions:

• cd-NDD pathology may arise from polygenic deviations that surpass adaptive variation limits during critical developmental stages.
• CNV models are crucial for dissecting the cell biological consequences of polygenic mutations in neurodevelopmental disorders.