Polymorphic CGG repeats in gene regulation and disease

Polymorphic CGG repeats, present at thousands of loci across the human genome, represent a distinctive class of regulatory DNA elements with dual roles in gene regulation and disease. Once regarded primarily as pathogenic triggers, CGG repeats are now recognized as modulators of transcription, chromatin state, and RNA metabolism. When expanded beyond normal thresholds, these repeats can drive neurodevelopmental and neurodegenerative disorders through transcriptional silencing, RNA toxicity, and repeat-associated non-AUG (RAN) translation. Recent advances in long-read sequencing have enabled comprehensive mapping of CGG repeat diversity, uncovering novel expansion loci and complex methylation and structural patterns underlying multiple human disorders. Together, these discoveries highlight CGG repeats as dynamic elements shaping gene expression, genome stability, and disease susceptibility. Emerging evidence further links CGG repeat expansions to non-neurological phenotypes, including cardiomyopathy, broadening their clinical significance. This review summarizes current understanding of CGG repeat polymorphisms in gene regulation and their mechanistic roles in disease, emphasizing both convergent and distinct pathogenic pathways across CGG expansion disorders.