Objective: We present the genetic testing diagnostic yield in a tertiary center Neurogenetic Clinic, focusing on rare movement disorders.

Background: The diagnostic yield of genetic testing for movement disorders is increasing as next-generation-sequencing (NGS) and advanced molecular testing are incorporated into routine work-up. We examine factors which effect diagnostic yield.

Method: Retrospective analysis (2019-2023) of 190 patients aged 1-84 years diagnosed with cerebellar ataxia (CA, N=92), spastic paraparesis (SPP, N=50) and hyperkinetic movement disorders, including dystonia and dyskinesia (HMD,N=48). Work-up included NGS and repeat expansion testing. Undiagnosed cases underwent exome-sequencing (ES) or genome-sequencing.

Results: Amongst 190 patients, 107 were newly referred undiagnosed patients. Amongst these a genetic diagnosis was reached in 46 cases (43%): 29 (63%) by NGS and 17 (37%) by repeat expansion analysis. Diagnostic rate reached 46% in CA, 31% in SPP and 32% in HMD. Diagnostic yield of NGS panels was 26% and of ES (singleton and trio) 33%. Diagnostic yield was higher among patients with younger onset of disease and isolated phenotypes. 29 patients had at least two brain MRI examinations during their work-up and 24 patients completed non diagnostic CMA tests.

Conclusion: Our Neurogenetic clinic reports higher diagnostic yield compared with reported literature (20-30%), especially in patients with early-onset disease. ES increased diagnostic yield, compared with panel testing, especially amongst patients with complex phenotypes. Our findings indicate that performing a tailored genetic work-up fashion according to phenotype complexity and age of onset can reduce the need for auxiliary and molecular testing. Further cost-benefit analysis is required to decrease expenses and ensure timely diagnosis.

Fig 1 Research Design and Yield

Fig 2 Diagnsotic yield correlations

References: Klein CJ, Foroud TM. Neurology Individualized Medicine: When to Use Next-Generation Sequencing Panels. Mayo Clin Proc. 2017 Feb;92(2):292-305
Ngo KJ, Rexach JE, Lee H, Petty LE, Perlman S, Valera JM, Deignan JL, Mao Y, Aker M, Posey JE, Jhangiani SN, Coban-Akdemir ZH, Boerwinkle E, Muzny D, Nelson AB, Hassin-Baer S, Poke G, Neas K, Geschwind MD, Grody WW, Gibbs R, Geschwind DH, Lupski JR, Below JE, Nelson SF, Fogel BL. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Hum Mutat. 2020 Feb;41(2):487-501

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MDS Abstracts - https://www.mdsabstracts.org/abstract/improving-work-up-amongst-patients-with-rare-movement-disorders-according-to-diagnostic-yield-findings-update-from-single-center-neurogenetic-clinic/