Objective:
Evaluate the utility of multigene Next-Generation Sequencing (NGS) for molecular diagnosis of parkinsonism and dystonia.

Background:
Parkinson’s disease (PD) and dystonia are common neurodegenerative disorders in adults. They have complex etiologies, and the contribution of specific monogenic causes and polygenic risk loci has not been systematically evaluated and established.

Method:
This retrospective study was performed on an unselected cohort of 553 individuals with parkinsonism and/or dystonia referred for molecular diagnostic testing. Age at testing ranged from 0.2- 92y (avg. 36.3y). Testing was performed by NGS and exon-level arrayCGH for one of these panels: PD (29 genes), Dystonia (53 genes), and Dystonia-Parkinsonism syndromes (73 genes).

Results:
Positive diagnostic results for each panel were obtained as follows: Dystonia: 19.4% (47/242), PD: 7.4% (10/136), and Dystonia-Parkinsonism: 7.4% (13/175). The majority (90%; 63/70) of positive cases had autosomal dominant disorders, most frequently involving the PRRT2 gene (24.3%; 17/70), with c.649dupC representing the most common variant (12/17). Overall, of 70 positive cases, more than one-third (25) had a treatable form of PD/dystonia with causative variants in LRRK2, GCH1, SNCA, PRKN, PINK1, SLC2A1 and ATP7B. LRRK2 was reported in multiple positive cases (6/70), all of which carried the recurrent p.G2019S variant (avg. age at testing 69.5y). GCH1 was reported in nine cases, of which eight were female, consistent with the reported sex-related penetrance (avg. age at testing 24.7y). Three patients had variants in the SNCA gene, causing early onset PD (avg. age at testing 42.8y) and 4 patients had two pathogenic variants in PRKN associated with autosomal recessive inheritance (avg. age at onset of 27.3y). Additionally, single heterozygous pathogenic variants in the GBA gene were found in 2.9% of patients (16/553), which is a known PD risk factor.

Conclusion:
Based on our results, genetic testing can identify monogenic causes in 7% -19% of individuals with parkinsonism and/or dystonia. This molecular information is crucial for medical management and optimized treatment approaches, may allow for inclusion in clinical trials, and for prognostic considerations, especially in slowly progressive or late onset disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/utility-of-multigene-panel-testing-for-diagnosing-parkinsonism-and-dystonia-in-a-large-cohort-of-500-patients/