A high-throughput sequencing panel targeting 127 genes associated with movement disorders is effective for identifying movement disorders and being less costly than whole-exome sequencing (WES) and whole-genome sequencing methods, according to a study in JAMA Neurology.
Patients with ≥1 chronic movement disorder with an age of onset of <40 years and/or a family history of movement disorders were enrolled (n=378). Each series of 24 samples of DNA associated with index cases were manually processed for library preparation. Only one lane of the Hiseq 4000 Sequencing System flow cell was used in the sequencing step for targeted sequencing of the 24 DNA samples. In addition, WES was performed for 6 samples.
A total of 127 genes implicated in movement disorders were selected to form a customized enrichment in solution capture array. Investigators worked to identify variants of unknown significance, many of which had a minor allele frequency <0.1% in the population and/or was pathogenic as determined by various prediction tools. Movement disorder groups included chorea, dystonia, myoclonus, parkinsonism, and paroxysmal movement disorder.
In 22% (n=83) of patients, probable pathogenic variants were identified. The predominant phenotype in the majority of these patients was parkinsonism (55%), followed by dystonia (25.3%), chorea (8.4%), paroxysmal movement disorders (8.4%), and myoclonus (2.4%). Patients with pathogenic variants were often younger (median age, 27 years; interquartile range [IQR], 5-36 years]) compared with patients with no pathogenic variants (median age, 35 years; IQR, 15-46 years; P =.04).
Individuals with dystonia had lower diagnostic yield compared with the entire cohort (15.6%; P =.03). There were 49 novel probable pathogenic variants identified. In patients with cerebellar ataxia (n=23), the WES resulted in a 26% overall diagnostic yield for pathogenic gene variants, which was similar in efficacy to that of the high-throughput sequencing panel. Despite no difference in efficacy, the WES was associated with a 6- to 7-times greater cost than the sequencing panel ($850-$1113/patient vs $156/patient, respectively).
Limitations of the analysis include the enrollment of mostly European patients and the small number of patients in each movement disorders group.
“Given the inconstant genotype-phenotype correlations, the frequency of combined movement disorders, and the overlaps, the relevance of targeted sequencing as a first intention test for the diagnosis of movement disorders should be considered,” the study investigators concluded.
Montaut S, Tranchant C, Drouot N, et al. Assessment of a targeted gene panel for identification of genes associated with movement disorders [published online June 18, 2018]. JAMA Neurol. doi: 10.1001/jamaneurol.2018.1478