Objective: This study investigates the prevalence and impact of short tandem repeat (STR) mutations in the next-generation sequencing data of patients with Parkinson’s disease (PD), essential tremor (ET), and amyotrophic lateral sclerosis (ALS) by analyzing a substantial dataset from over 14,000 unrelated individuals.

Background: Emerging evidence suggests that additional heritable factors remain to be identified in PD, ET and ALS, except for SNPs and Indels. To date, 63 STR loci associated with diseases have been identified, with half of these implicated in neurological diseases. [1, 2]

Method: The study cohort comprised 6,278 patients with PD, 1,384 patients with ET, 359 patients with ALS, and 6,658 healthy controls from the PD-MDCNC database (http://pd-mdcnc.com/) [3, 4]. Whole-exome sequencing (WES) or whole-genome sequencing (WGS) was performed on them. ExpansionHunter and str-analysis software were used to analyze all known disease-associated STR loci [5, 6]. Polymerase chain reaction (PCR) genotyping was employed to validate predicted repeat sizes.

Results: The analysis revealed that approximately 7.77% of patients with PD exhibited pathogenic or intermediate STR expansions, with 44 clinically diagnosed PD cases confirmed with pathogenic STR expansions in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN8OS, PPP2R2B, THAP11, FMR1, HTT, AR, NOTCH2NLC, and GIPC1. In the ET cohort, approximately 11.39% showed pathogenic or intermediate STR expansions, with 29 clinically diagnosed ET cases validated with pathogenic STR expansions in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN8OS, PPP2R2B, FMR1, AR, NOTCH2NLC, GIPC1, DMPK, SAMD12, and RFC1. Additionally, in ALS patients, 14.21% STRs exhibited pathogenic or intermediate STR expansions, with nine clinically diagnosed ALS cases were identified and validated with pathogenic STR expansions in C9ORF72, AR, DMPK, CBL, ATXN8OS, and GIPC1. (figure 1) Interestingly, An intermediate expansion in the ATXN3 locus for PD and ATN1 locus for ET requires further study as a potential risk for disease onset. (figure 2).

Conclusion: This study provides novel insights into the role of STRs mutations in neurodegenerative diseases, potentially impacting clinical diagnosis, treatment, and prevention strategies for PD, ET, or ALS. The findings emphasize the importance of continued research to better understand the genetic underpinnings of these conditions.

Distribution of STR expansion size

Comparsion of ATXN3 or ATN1 expansion frequencies

References: [1] Ibanez K, Polke J, Hagelstrom RT, et al. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 2022; 21: 234-45.
[2] van der Sanden B, Corominas J, de Groot M, et al. Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield. Genet Med. 2021; 23: 1569-73.
[3] Zhao Y, Qin L, Pan H, et al. The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population. Brain. 2020; 143: 2220-34.
[4] Zhou X, Liu Z, Zhou X, et al. The Chinese Parkinson’s Disease Registry (CPDR): Study Design and Baseline Patient Characteristics. Movement disorders : official journal of the Movement Disorder Society. 2022; 37: 1335-45.
[5] Dolzhenko E, Deshpande V, Schlesinger F, et al. ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions. Bioinformatics. 2019; 35: 4754-6.
[6] Shi Y, Niu Y, Zhang P, et al. Characterization of genome-wide STR variation in 6487 human genomes. Nat Commun. 2023; 14: 2092.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unraveling-the-role-of-short-tandem-repeats-in-parkinsons-disease-essential-tremor-and-amyotrophic-lateral-sclerosis-a-large-chinese-cohort-study/