Montaut S, et al. - The current study explored developing a targeted sequencing approach using a customized panel of genes involved in movement disorders. Researchers reported that high-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.

Methods

• For this investigation, 127 genes associated with movement disorders were selected to generate a customized enrichment in solution capture array.
• Between September 2014 and July 2016, DNA samples were taken from 378 eligible subjects at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers, which then had targeted high-coverage sequencing applied to them.
• Because of early onset, family history, and/or complex phenotypes, patients were suspected of having inherited movement disorders.
• Patients were divided into five main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus.
• Twenty-three additional patients suspected of having inherited cerebellar ataxia were involved; whole-exome sequencing (WES) was done on these patients to compare approaches.
• From November 2015 to October 2016, data was analyzed.
• Percentages of individuals with positive diagnosis, variants of unknown significance, negative cases, mutational frequencies, and clinical phenotyping of genes correlated with movement disorders were the main outcomes and measures.

Results

• According to the findings, out of 378 subjects (208 male [55.0%]) with a median (range) age at disease onset of 31 (0-84) years, likely pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype.
• It was noted that some genes were mutated in several cases in the cohort.
• Researchers found that patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years) than those without diagnosis (median age, 35 years; IQR, 15-46 years; P=.04).
• Compared to the overall cohort, diagnostic yield was observed to be significantly lower in those with dystonia (21 of 135; 15.6%; P=.03).
• Findings revealed that unexpected genotype-phenotype associations in patients with pathogenic variants different from the classic phenotype were underscored, and 49 novel likely pathogenic variants were detected.
• The WES analysis of the cohort of 23 subjects with cerebellar ataxia led to an overall diagnostic yield of 26%, like panel analysis, but at a cost six to seven times greater.