Objective: To investigate the effect of genetic modifiers of X-linked dystonia-parkinsonism (XDP) on the relevant repeat across generations.

Background: XDP is a rare neurodegenerative disorder caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion. A hexameric repeat in the SVA is the major modifier of age at onset (AAO) in XDP. Intergenerational repeat instability favors expansions in maternal transmissions, while paternal transmissions are more likely to retain the repeat length or contract than to expand. DNA mismatch repair proteins encoded by MSH3 and PMS2 influence repeat instability in expansion disorders, and SNPs within or near these genes (rs245013, rs33003, and rs4724769) are linked to XDP AAO and tag respective genetic modifiers.

Method: We studied 70 XDP families with 108 intergenerational transmissions. Hexanucleotide repeat numbers and SNP genotypes were determined. Repeat number changes from parent to child were classified as expansion, retention, or contraction. Statistical analyses included the Mann–Whitney U test, Fisher’s Exact test, and linear regression.

Results: Maternal transmissions (n=89, 62% expansions vs. 2% contractions) showed a mean repeat increase of 0.78, while paternal transmissions (n=19, 47% expansions vs. 32% contractions) had a smaller mean increase of 0.50 repeats. Nonetheless, the mean repeat increase per generation (<1 repeat) did not vary by parent (p=0.28). However, the direction of repeat instability differed significantly by parent of origin (p=0.0008).  Maternal repeat length had a small, non-significant effect on the direction of intergenerational repeat change (β=0.05, p=0.072), which remained nonsignificant after SNP adjustment. Analyses of maternal transmissions identified two SNPs that alter repeat change direction, with rs245013 driving expansion (β=0.39, p=0.035) and rs4724769 favoring contraction or retention (β=-0.59, p=0.009). Paternal repeat changes were not significantly affected by SNPs (R²=0.07), likely due to small sample size.

Conclusion: MSH3 and PMS2 genetic modifiers affect maternally transmitted repeat stability, as rs245013 promotes expansion while rs4724769 protects against it. The direction of these modifiers’ effects aligns with their impact on AAO, indicating they indeed influence AAO through repeat instability. Along with parent-of-origin patterns, these findings may improve risk prediction in XDP families.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modifiers-of-intergenerational-repeat-changes-in-x-linked-dystonia-parkinsonism/