Sex differences in the developing human cortex intersect with genetic risk of neurodevelopmental disorders

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) is highly heritable and diagnosed more frequently in males.
• Understanding sex-biased vulnerability in neurodevelopmental disorders (NDDs) is crucial.

Purpose of the Study:

• To identify molecular mechanisms underlying sex differences in NDD vulnerability.
• To investigate the role of prenatal brain development in sex-biased autism risk.

Main Methods:

• Generated transcriptomic and epigenomic profiles of the developing human cerebral cortex from male and female samples.
• Intersected sex-biased molecular signatures with de novo mutations in autistic individuals.
• Constructed gene regulatory maps for X-linked NDD risk genes.

Main Results:

• NDD risk genes show higher expression in females, with MEF2C identified as a key transcription factor.
• X chromosome genes significantly contribute to NDD pathobiology.
• Identified distinct vulnerability mechanisms: coding variation in females and noncoding variation in males.

Conclusions:

• The X chromosome plays a significant role in both sex differences in brain development and NDD vulnerability.
• Proposes a model where coding variation drives female-biased NDD risk, while noncoding variation drives male-biased risk.