MAZA, A. M.; Hincher, M.; Correia, K.; Gillis, T.; Nishiyama, A.; Penney, E. B.; Domingo, A.; Yadav, R.; Murcar, M. G.; Mercado, P.; Han, J. S.; Norenberg, E. P.; Fernandez-Cerado, C.; Legarda, G. P.; Sy, M.; Munoz, E.; Ang, M. C.; Diesta, C. C. E.; Go, C.; Sharma, N.; Bragg, D. C.; Talkowski, M. E.; MacDonald, M. E.; LEE, J.-M.; Ozelius, L. J.; Wheeler, V. C.

X-linked dystonia parkinsonism (XDP) is a progressive adult-onset neurogenerative disorder caused by the insertion of a SINE-VNTR-Alu (SVA) retrotransposon in TAF1 gene. One element of the SVA is a tandem polymorphic CCCTCT repeat tract whose length inversely correlates with the age of disease onset. Previous observations that the repeat exhibits length-dependent somatic expansion and that XDP onset is modified by variation in DNA repair gene MSH3 indicated that somatic repeat expansion is an important disease driver. Here, we sought to uncover genetic modifiers of CCCTCT instability in XDP patients and to provide a mechanistic link between somatic instability and disease. We determined quantitative metrics of both repeat expansion and repeat contraction in blood. Using genetic association analyses of exome sequencing data, as well as directed sequencing of a variant MSH3 repeat, we found that MSH3 modifies repeat expansion and contraction in blood as well as age at onset. MSH3 alleles associated with earlier disease onset were associated with more expansion and less contraction. Conversely, alleles associated with later disease onset were associated with less expansion and more contraction. Notably, MSH3 repeat alleles were also similarly associated with expansion and contraction in brain tissues. Our findings provide key evidence that MSH3 role(s) in CCCTCT repeat dynamics underlies its impact on clinical disease and indicate that therapeutic strategies to lower or inhibit MSH3 are predicted to both slow CCCTCT expansion and promote CCCTCT contraction, impacting the disease course prior to clinical onset.