What Are The Implications Of CGG Repeat Expansions In The FMR1 Gene On The Methylation Patterns Of The Upstream Exon 1 Region, And How Do These Epigenetic Modifications Correlate With The Severity Of Cognitive And Behavioral Symptoms In Males With Full-mutation Fragile X Syndrome?

The CGG repeat expansion in the FMR1 gene, typically exceeding 200 repeats, leads to Fragile X Syndrome (FXS) by triggering hypermethylation of the gene's promoter and upstream regions, including exon 1. This methylation silences FMR1, preventing the production of the FMRP protein, which is crucial for synaptic function and brain development. The absence of FMRP results in cognitive and behavioral symptoms such as intellectual disability and autism spectrum disorder.

The extent of methylation correlates with symptom severity: greater methylation is associated with more severe symptoms due to reduced FMRP production. However, variability exists due to factors like mosaicism, where some cells may retain FMR1 expression, leading to milder symptoms. Additionally, the timing of methylation during development can influence symptom severity, with early methylation potentially causing more severe effects.

In summary, the hypermethylation of FMR1's upstream region, including exon 1, silences the gene, leading to FXS. The degree of methylation and individual factors like mosaicism affect the severity of symptoms, with more methylation generally correlating with worse outcomes.