Brain Regional Differences in Hexanucleotide Repeat Length in X-Linked Dystonia-Parkinsonism Using Nanopore Sequencing

Charles Jourdan Reyes; Björn-Hergen Laabs; Susen Schaake; Theresa Lüth; Raphaela Ardicoglu; Aleksandar Rakovic; Karen Grütz; Daniel Alvarez-Fischer; Roland Dominic Jamora; Raymond L Rosales; Imke Weyers; Inke R König; Norbert Brüggemann; Christine Klein; Valerija Dobricic; Ana Westenberger; Joanne Trinh

doi:10.1212/NXG.0000000000000608

Brain Regional Differences in Hexanucleotide Repeat Length in X-Linked Dystonia-Parkinsonism Using Nanopore Sequencing

Neurol Genet. 2021 Jul 6;7(4):e608. doi: 10.1212/NXG.0000000000000608. eCollection 2021 Aug.

Authors

Charles Jourdan Reyes¹, Björn-Hergen Laabs¹, Susen Schaake¹, Theresa Lüth¹, Raphaela Ardicoglu¹, Aleksandar Rakovic¹, Karen Grütz¹, Daniel Alvarez-Fischer¹, Roland Dominic Jamora¹, Raymond L Rosales¹, Imke Weyers¹, Inke R König¹, Norbert Brüggemann¹, Christine Klein¹, Valerija Dobricic¹, Ana Westenberger¹, Joanne Trinh¹

Affiliation

¹ Institute of Neurogenetics (C.J.R., S.S., T.L., R.A., A.R., K.G., D.A.-F., N.B., C.K., V.D., A.W., J.T.), University of Lübeck, and Institute of Medical Biometry and Statistics (B.-H.L., I.R.K.), University of Lübeck, Germany; Department of Neurosciences (R.D.J.), College of Medicine-Philippine General Hospital, University of the Philippines Manila; Department of Neurology and Psychiatry (R.L.R.), University of Santo Tomas Hospital, Manila, Philippines; Institute of Anatomy (I.W.), Department of Neurology (N.B.), and Lübeck Interdisciplinary Platform for Genome Analytics (V.D.), University of Lübeck, Germany.

Abstract

Objective: Our study investigated the presence of regional differences in hexanucleotide repeat number in postmortem brain tissues of 2 patients with X-linked dystonia-parkinsonism (XDP), a combined dystonia-parkinsonism syndrome modified by a (CCCTCT)_n repeat within the causal SINE-VNTR-Alu retrotransposon insertion in the TAF1 gene.

Methods: Genomic DNA was extracted from blood and postmortem brain samples, including the basal ganglia and cortex from both patients and from the cerebellum, midbrain, and pituitary gland from 1 patient. Repeat sizing was performed using fragment analysis, small-pool PCR-based Southern blotting, and Oxford nanopore sequencing.

Results: The basal ganglia (p < 0.001) and cerebellum (p < 0.001) showed higher median repeat numbers and higher degrees of repeat instability compared with blood.

Conclusions: Somatic repeat instability may predominate in brain regions selectively affected in XDP, thereby hinting at its potential role in disease manifestation and modification.