Objective: This study aimed to assess the diagnostic yield of commercially available genetic panels in dystonia patients and how test performance varies across dystonia subtypes.

Background: Dystonia is a genetically heterogeneous movement disorder with variable clinical presentations. However, the diagnostic yield of genetic testing varies with panel composition and patient selection, and the effectiveness of commercially available panels across dystonia subtypes remains uncertain. This underscores the need for a systematic assessment within a clinical cohort.

Method: We retrospectively reviewed 139 dystonia patients seen at Toronto Western Hospital (2015-2024), including 21 patients with Parkinson’s disease exhibiting dystonic features. All underwent next-generation sequencing using commercially available genetic panels, which (32-226 genes, median: 38). The mean age-at-onset was 29.01 ± 19.93 years. Patients were categorized into focal dystonia (N=53), segmental/hemidystonia (N=45), generalized dystonia (N=33), and paroxysmal kinesigenic dyskinesia (PKD, N=8). Diagnostic yield was calculated for each subgroup and, patients were further stratified using a predictive clinical score ¹, based on age-at-onset, dystonia distribution, and the presence of additional neurological symptoms (maximum score 5).

Results: The overall diagnostic yield was 12% (17/139). Stratification by dystonia subtype revealed a low yield in focal dystonia (1.9%), whereas segmental/hemidystonia and generalized dystonia yielded 17.8–18.2%. Among 21 Parkinson’s disease patients with dystonic features (16 focal), a genetic diagnosis was made in 9.5% (2/21), including one case with a homozygous PINK1 c.1040T>C mutation. In segmental dystonia, SGCE mutations were found in three patients, GCH1 in two patients and singular cases carrying variants in TOR1A, and ATP1A3. In generalized dystonia, pathogenic variants were identified in SQSTM1, DCAF17, THAP1, GDAP2, and a homozygous deletion in PRKN; one patient was diagnosed with a complex mitochondrial disorder. The diagnostic yield increased with higher predictive clinical score: 5.6% for scores 0–2 (n=72), 14.0% for scores 3–4 (n=43), and 29.0% for a score of 5 (n=24).

Conclusion: Genetic testing shows higher diagnostic yield in dystonia patients with broader involvement and higher predictive clinical score, but its limited utility in focal dystonia highlights the need for improved patient selection.

References: 1. Zech M, Jech R, Boesch S, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 2020;19(11):908-918.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/diagnostic-yield-of-commercial-genetic-testing-for-dystonia-in-a-canadian-movement-disorders-cohort/