Diagnostic Yield of a Targeted Next-Generation Sequencing Gene Panel for Pediatric-Onset Movement Disorders: A 3-Year Cohort Study

Abstract

In recent years, genetic techniques of diagnosis have shown rapid development, resulting in a modified clinical approach to many diseases, including neurological disorders. Movement disorders, in particular those arising in childhood, pose a diagnostic challenge. First, from a purely phenomenological point of view, the correct clinical classification of signs and symptoms may be difficult and require expert evaluation. This is because the clinical picture is often a mixture of hyperkinetic and hypokinetic disorders, and within hyperkinetic movement disorders, combined phenotypes are not unusual. Second, although several genes that cause movement disorders in children are now well-known, many of them have only been described in adult populations or discovered in patients after many years of disease. Furthermore, diseases that alter their mechanisms from childhood to adulthood are still little known, and many phenotypes in children are the result of a disruption of normal neurodevelopment. High-throughput gene screening addresses these difficulties and has modified the approach to genetic diagnosis. In the exome-sequencing era, customized genetic panels now offer the ability to perform fast and low-cost screening of the genes commonly involved in the pathogenesis of the disease. Here, we describe a 3-year study using a customized gene panel for pediatric-onset movement disorders in a selected cohort of children and adolescents. We report a satisfying diagnostic yield, further confirming the usefulness of gene panel analysis.

Keywords: children; chorea; dystonia; genetics; myoclonus; neurodegeneration with brain iron accumulation disorders; neurotransmitters; next-generation sequencing.

Figure 1

Number and percentage of the total patients by classification according to prominent MD phenomenology. Following the phenomenology of the attacks, the paroxysmal MD group is further classified into episodic ataxia (EA), paroxysmal kinesigenic dyskinesia (PKD), and exercise-induced paroxysmal dyskinesia (EPD), hemiplegic attacks, and paroxysmal myoclonus groups. MD, movement disorder.

Figure 2

Associated neurological features of the cohort and diagnostic yield of the gene panel analysis. (A) Associated neurological features in the overall cohort. (B) Diagnostic yield in the overall cohort and in the different groups, expressed as total number of patients receiving a definite molecular diagnosis through gene panel analysis. (C) Diagnostic yield of gene panel analysis in paroxysmal MD according with their phenomenological classification. (D) Distribution of pathogenetic variants encountered per gene (see Appendix 2 in the Supplementary Materials for the complete list of genes sequenced in the panel). DD, developmental delay; EA, episodic ataxia; EPD, exercise-induced paroxysmal dyskinesia; ID, intellectual disability; MD, movement disorder; PKD, paroxysmal kinesigenic dyskinesia.