Complex associations of genetic/epigenetic variations of CGG repeats with patient phenotypes in oculopharyngodistal myopathy

Oculopharyngodistal myopathy (OPDM) is caused by CGG triplet repeat expansions in six genes. To explore the genetics and epigenetics of OPDM, we conducted CRISPR/Cas9-targeted resequencing of repeat regions in 89 patients. Repeat regions essentially comprised pure CGG expansions, but exhibited size variability, even within patients. Expanded LRP12 and GIPC1 alleles showed distinct single nucleotide variant patterns, suggesting founder haplotypes. LRP12-expanded reads lacked flanking sequences present in non-expanded reads, whereas GIPC1 expanded repeats contained specific nucleotide patterns in their 5-regions. Structural variations were identified in some patients. A significant inverse correlation was observed between repeat length and age at onset in patients with GIPC1 or NOTCH2NLC expansions, while this was disturbed by higher methylation of expanded regions in patients with LRP12 expansions, leading to delayed onset. These findings reveal a complex interplay among repeat size, sequence context, and epigenetic state in OPDM pathogenesis, advancing knowledge and providing opportunities for therapeutic intervention.