REPEAT EXPANSION IN MYOTONIC DYSTROPHY: Exploration of Genetic Modifiers of Repeat Instability

Abstract

Congenital myotonic dystrophy (CDM), the most severe form of myotonic dystrophy type 1 (DM1), arises from rapid intergenerational expansions of CTG repeats in the DMPK gene. This study leverages the largest whole-exome sequencing (WES) cohort of CDM cases to date to elucidate genetic modifiers of repeat instability and contributors to clinical phenotype. Variant burden analysis, allele frequency comparisons, and permutation testing revealed the enrichment of rare variants in DNA repair and muscle integrity pathways, with MSH6, NEBL, and SGCG emerging as key candidates. Functional enrichment highlighted disruptions in mismatch repair (MMR), homologous recombination, and replication-associated processes, implicating these pathways in both germline and somatic instability. Two lines of evidence implicate MSH3 in CDM pathogenesis: a deleterious variant identified in a multigenerational pedigree cosegregating expanded DMPK alleles and demonstrating impaired DNA repair capacity in functional assays and a strong prevalence of an MSH3 haplotype (including the rs1650697 variant) previously linked to contrasting effects, delayed onset in Huntington’s Disease and earlier onset in DM1. Correlation analyses revealed a compelling dichotomy: rare MMR variants are associated with smaller expansions, predominantly in DM1 mothers, suggesting a germline influence; in contrast, replication stress-related genes correlated with larger expansions characteristic of CDM, reflecting somatic instability. These findings underscore two central themes: disruption of DNA repair machinery and compromised muscle integrity as potential modifiers of repeat instability and the CDM phenotype. Together, this integrative approach, which combines statistical enrichment, family-based variant sharing, and functional validation, advances the understanding of CDM pathogenesis and highlights MSH3, a known modifier of repeat instability, as a promising target for therapeutic modulation with distinct effects in CDM compared to other repeat expansion disorders