A massively parallel reporter assay of MECP2cis-regulatory elements reveals genetic candidates for male-biased autism.

Two noncoding MECP2 variants linked to male-biased autism phenotypes, with one reducing gene expression by approximately 30%.

• Why it matters: Understanding genetic factors behind the fourfold higher prevalence of autism in males is crucial for uncovering the biological basis of sex bias in neurodevelopmental disorders.
• What they did: Researchers used a massively parallel reporter assay in human neurons to map transcription factor binding sites within MECP2 cis-regulatory elements and tested autism-associated variants for functional effects, identifying two impactful noncoding variants.
• The result: One variant disrupts NFY binding, decreases MECP2 expression by about 30%, and produces social deficits, hyperactivity, and anxiety-like behaviors in mice, suggesting noncoding MECP2 variants may contribute to male-biased autism.