Objective: To assess the breadth of presentations to a tertiary neurogenetics clinic and evaluate the diagnostic yield of whole-genome sequencing (WGS) in genetic movement disorders.

Background: Obtaining a molecular diagnosis is often challenging in genetic movement disorders given the clinical and genetic heterogeneity (1,2).  The recent mainstreaming of WGS in routine clinical care in England has expanded opportunities to improve molecular diagnosis (3,4,5,6).

Method: Medical records for patients referred to our tertiary neurogenetics clinic over a six month period in 2023 were reviewed. Data collected included age and phenotype at presentation, genetic testing method used, and if a genetic diagnosis was obtained.

Results: 250 patients were reviewed (56.4% female, mean (SD) age at onset: 28.3 years (19.0)). Half had a family history of similar symptoms. Over half of symptomatic patients presented with a movement disorder (52.6%). The most common clinical phenotypes were ataxia (27.2%) and hereditary spastic paraparesis (20.5%). 17 unaffected individuals presented for genetic counselling.

214 patients with symptoms received diagnostic genetic testing: 110 WGS, with the rest using non-WGS methods (including NGS gene panels and single gene testing). 56.9% patients received a genetic diagnosis. All at-risk individuals received confirmation of their genetic status. The diagnostic yield of WGS was 34.7%. Of the WGS-positive diagnosed individuals, almost half had been unsolved cases despite previous (non-WGS) genetic testing. Of interest, three individuals who initially had negative WGS reports were re-analysed for variants in new gene panels and found to have a positive diagnosis. One previously identified VUS underlying a complex parkinsonian syndrome was confirmed with WGS as pathogenic. The diagnostic yield of WGS was higher for movement disorders than non-movement disorders presentations (38.5% vs 29.2%).

Conclusion: A significant proportion of neurogenetic disorder burden arises from movement disorders. WGS may have particular diagnostic utility in movement disorders compared to other neurogenetic conditions given their genetic heterogeneity and wide range of clinical manifestations. Systematic re-analysis of inconclusive WGS data with updated genetic panels of undiagnosed individuals further increases the diagnostic yield of rare neurogenetic conditions (7).

References: 1. Waung MW, Ma F, Wheeler AG, Zai CC, So J. The Diagnostic Landscape of Adult Neurogenetic Disorders. Biology (Basel). 2023;12(12).
2. Morris HR, Houlden H, Polke J. Whole-genome sequencing. Pract Neurol. 2021;21(4):322–6.
3. NHS Genomic Medicine Service [Internet]. [cited 2025 Mar 11]. Available from: https://www.england.nhs.uk/genomics/nhs-genomic-med-service/
4. Cipriani et al. Rare disease gene association discovery in the 100,000 Genomes Project. Nature. 2025 https://doi.org/10.1038/s41586-025-08623-w
5. Smedley et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care – Preliminary Report. New England Journal of Medicine. 2021;385(20):1868-1880.
6. Turro et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature. 2020 Jul;583(7814):96-102.
7. Kauffman JM et al. The odyssey of complex neurogenetic disorders: From undetermined to positive. Am J Med Genet. 2020;184(4):876–84.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/diagnostic-yield-of-whole-genome-sequencing-in-genetic-movement-disorders/