Functional impact of genetic background on variable expressivity in neurodevelopmental disorders

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Variable phenotypic outcomes in neurodevelopmental disorders are linked to disease-associated variants.
• The underlying biological mechanisms driving this phenotypic variability are not well understood.

Purpose of the Study:

• To develop a framework for investigating phenotypic variability in neurodevelopmental disorders.
• To use the 16p12.1 deletion as a model for variable expressivity.

Main Methods:

• Utilized induced pluripotent stem cell (iPSC) models from affected families and CRISPR-edited cell lines.
• Analyzed chromatin accessibility and gene expression.
• Performed cellular analyses to identify family-specific phenotypes.
• Employed CRISPR activation to modulate gene expression and rescue cellular defects.
• Conducted integrative analyses to identify regulatory hubs.

Main Results:

• The 16p12.1 deletion and background genetic variants synergistically affect chromatin accessibility and neurodevelopmental gene expression.
• Identified family-specific cellular phenotypes, including altered inhibitory neuron production and neural progenitor cell proliferation, correlating with head-size variation.
• Demonstrated that CRISPR activation of individual 16p12.1 genes can variably rescue defects by modulating developmental signaling pathways.
• Identified transcription factors FOXG1 and JUN as key mediators.

Conclusions:

• Established a functional framework to study how individual genetic architectures contribute to phenotypic variability in neurodevelopmental disorders.
• Highlighted the interplay between deletions, rare variants, and gene regulation in shaping neurodevelopmental phenotypes.