Category: Parkinson's Disease: Genetics
Objective: To investigate the utility of long-read single-molecule nanopore sequencing for simultaneous detection of repeat number and methylation of the SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene in X-linked dystonia-parkinsonism (XDP) patients.
Background: XDP is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. XDP is caused by a single founder mutation: an SVA retrotransposon insertion in the TAF1gene. Furthermore, the length of the polymorphic (CCCTCT)n domain within the TAF1 SVA retrotransposon acts as a genetic modifier of disease expressivity in XDP.
Method: Cas9-targeted enrichment was used to retain epigenetic modifications within and around the TAF1 SVA. CpG methylation within and around the SVA was detected in multiple tissue types (blood, basal ganglia and cerebellum) for a single patient. Blood-derived DNA of a patient without an SVA insertion was used as a control. Lastly, fragment analysis and nanopore sequencing of the PCR-amplified SVA insertion was performed on 39 XDP patients.
Results: The median methylation frequency within the SVA is 0.912 (SD: 0.109) before the polymorphic (CCCTCT)n domain. The median methylation frequency upstream of the SVA (0.718, SD: 0.196) is lower than the median methylation frequency within the SVA. The median methylation at a predicted enhancer site upstream of the SVA differs between tissue-derived DNA (0.746, SD: 0.204) and blood-derived DNA (0.820, SD: 0.153). Lastly, the median repeat numbers obtain through nanopore and fragment analyses show high concordance.
Conclusion: Nanopore sequencing can detect repeat number and epigenetic modifications. Somatic differences in methylation across tissues suggest mechanisms of differential TAF1 expression implicated in XDP.
To cite this abstract in AMA style:
J. Laß, T. Lüth, S. Schaake, J. Pozojevic, A. Westenberger, J. Trinh, C. Klein. Utility of the long-read single-molecule nanopore sequencing for detection of repeat number and epigenetic modifications relevant for X-linked dystonia-parkinsonism [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/utility-of-the-long-read-single-molecule-nanopore-sequencing-for-detection-of-repeat-number-and-epigenetic-modifications-relevant-for-x-linked-dystonia-parkinsonism/. Accessed November 9, 2026.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/utility-of-the-long-read-single-molecule-nanopore-sequencing-for-detection-of-repeat-number-and-epigenetic-modifications-relevant-for-x-linked-dystonia-parkinsonism/