Objective: This study aims to investigate the stability of Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) frequencies and repeat length across generations and lifetime in families with X-linked dystonia-parkinsonism (XDP).

Background: XDP is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. The hexanucleotide repeat domain, (AGAGGG)_n, within the TAF1 SVA retrotransposon is a disease modifier. mDRILS were recently found to be present within the repeat motif of the TAF1 SVA and associated with repeat stability and age at onset in XDP, expecially the AGGG [5’-SINE-VNTR-Alu(AGAGGG)₂AGGG(AGAGGG)_n] mDRILS.

Method: Thirteen father-daughter families and 43 mother-son families (n=130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals were anaylzed at two time points, in average one year apart. Blood-derived DNA was sequenced with Oxford Nanopore long-read technologies (SQK-LSK109, R9.4.1) after long-range PCR amplification of the TAF1 SVA. Repeat number and mDRILS were detected with NCRF v1.01.02.

Results: When comparing the repeat domain, 42 out of 72 children had either contractions or expansions. Of the 42 children, four children had fewer hexanucleotide repeats compared to their parents (contractions), and 38 children had more repeats (expansions). The AGGG remained stable across generations at a frequency of 0.074 (IQR:0.069-0.078, p=0.364). However, the median AGGG frequency in children with an expansion (0.072 (IQR:0.063-0.076)) differed from children with retention (0.075 (IQR:0.070-0.083), p=0.022). Children with a contraction had the highest at 0.079 (IQR:0.074-0.085). The AGGG frequency is associated with the gender of the children (p=2.132×10^-5). The repeat number across two time points remained stable. In contrast, the AGGG frequency varied slightly over time ranging from 0.070 (IQR:0.063-0.079) to 0.072 (IQR:0.069-0.078).

Conclusion: Our results show that the AGGG frequency negatively correlates with generational expansions of the hexanucleotide repeat number and positively correlates with contractions, which suggests protective mechanisms of the AGGG mDRILS with respect to disease onset. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mosaic-divergent-repeat-interruptions-in-x-linked-dystonia-parkinsonism-stability-over-generations-and-time/