High Genetic Diagnostic Yield for Patients with Rare Movement Disorders at a Single-Center Neurogenetics Clinic

As advanced molecular testing is incorporated into routine clinical practice, accessibility and yield remain limited.

We propose a simplified and effective workup strategy to maximize diagnostic yield based on presented diagnostic yield of rare movement disorders at a tertiary Neurogenetics Clinic.

Retrospective analysis (2019-2023) of 190 patients aged 2-87 years, diagnosed with cerebellar ataxia (CA, n = 91), hereditary spastic paraparesis (HSP, n = 51), or dystonia and paroxysmal dyskinesia movement disorders (DPD, n = 48). Workup included next-generation sequencing (NGS) and repeat expansion testing. Undiagnosed cases underwent exome or genome sequencing (ES/GS).

Among 190 patients, 38 had a prior genetic diagnosis, and 106 were undiagnosed patients who pursued workup; 43 of 106 (41%) cases were genetically diagnosed: 25 of 43(58%) by NGS, 13 of 43 (30%) by repeat expansion analysis, and 5 of 43(12%) by sequencing for founder mutation or target gene. Diagnostic rate in the newly diagnosed CA subgroup reached 52%, 30% in HSP and 32% in DPD. In the overall cohort, the diagnostic yield of NGS panels was 31% and 33% for ES. Diagnostic yield was significantly higher (P-value<0.05) among patients with early-onset disease or isolated phenotypes.

We report a high diagnostic yield (41%) compared to reported literature (20%-30%), especially in patients with early-onset disease. ES, compared to panel testing, was of greater contribution to diagnosis of complex phenotypes. Our findings argue for early referral to genetic workup, suggesting that tailored workup based on phenotype complexity and age of onset can reduce auxiliary testing. Further cost-benefit analysis is required to lower expenses and ensure timely diagnosis.