Objective: To evaluate the diagnostic utility of whole-exome sequencing (WES) in select patients with a movement disorder.

Background: Many patients with suspected genetic movement disorders do not have a known molecular diagnosis, which can significantly impact patients and their families. An accurate genetic diagnosis can guide treatment, provide prognostic information as well as inform genetic counseling for at-risk family members.

Method: We performed a retrospective chart review of movement disorder patients evaluated in our clinic with WES analyzed between January 2013 and December 2020.

Results: Among the 41 patients with WES orders after neurological evaluation, 28 patients (57.1% male) had complete WES results; the other 13 (31.7%) were denied approval by their insurance company. Median age at symptom onset was 20.5 years (range 0.04-63 years) and median age at testing was 45.5 years (range 4-69 years). A positive family history of a movement disorder in a first or second-degree relative was noted in 57.1% of patients. Approximately 46% of patients had undergone targeted genetic testing prior to WES. The dominant movement disorder phenotypes for which WES was completed were as follows: dystonia (50%), parkinsonism (21.4%), myoclonus (14.3%), and ataxia (10.7%).   We identified 4 pathogenic variants and 1 novel variant of unknown significance (VUS) in PANK2, SPG11, PSEN1, TOR1A, and GLRA1 genes that were diagnostic in 5 out of 28 patients, achieving a molecular diagnostic yield of 17.9%.

Conclusion: WES has an important diagnostic value in movement disorder patients with atypical presentation and high index of suspicion for a genetic etiology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/whole-exome-sequencing-in-a-movement-disorders-clinic/