NEW YORK (GenomeWeb) – Targeted gene panels could offer a cost-effective approach for the diagnosis of movement disorders.
Movement disorders — which include conditions such as dystonia or parkinsonism — can be acquired or inherited, and they are often clinically and genetically heterogeneous, which can make clinical diagnosis challenging.
Researchers from the French Parkinson's and Movement Disorders Consortium created a 127-gene panel for movement disorders, which they used to diagnose nearly 400 patients. As they reported today in JAMA Neurology, this approach had a diagnostic yield of 22 percent and cost about $156 per patient before labor costs.
"[A h]igh-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," senior author Mathieu Anheim from the University Hospitals of Strasbourg and his colleagues wrote in their paper.
The researchers collected DNA samples from 378 patients with suspected movement disorders from hospitals in France, Luxembourg, and Algeria. To be included, the patients not only had to present with at least one chronic movement disorder, but also had to have an age of onset of younger than 40 years or have a family history of movement disorders.
The researchers classified the patients in the cohort based on their prominent type of movement disorder: parkinsonism, dystonia, chorea, paroxysmal movement disorders, or myoclonus. They then analyzed the samples they collected from the cohort using a custom enrichment in-solution capture array they developed that targeted 127 genes associated with movement disorder — including the Parkinson disease-linked PARKIN, LRRK2, and GBA genes — combined with sequencing on the Illumina HiSeq 4000 platform. For this cohort, the researchers generated a mean depth of coverage of 1,266X and a mean 99.7 percent of targeted regions had more than 30X coverage in each patient.
Though nearly 40 percent of the cohort had already undergone genetic testing, the researchers detected pathogenic variants in 83 patients, giving them an overall diagnostic yield of 22 percent.
Some disorder subtypes fared better in diagnosis than others: the parkinsonism group had a diagnostic yield of 25.4 percent, but the dystonia group only had a yield of 15.6 percent. Those who could be diagnosed tended to have a lower age of onset and were more likely to have a family history of disease.
Seventeen patients had variants in PARKIN, nine had variants in GBA, and eight had variants in LRRK2. No pathogenic variants were found in 244 patients, and for 60 other patients, the analysis uncovered variants of unknown significance.
For comparison, the researchers sequenced the whole exomes of 23 patients with predominantly recessive cerebellar ataxia, which had an overall diagnostic yield of 43.5 percent. However, when they combined it with additional data from a similar whole-exome sequencing analysis of 76 patients, the overall diagnostic yield fell to 26.3 percent — about the same as their targeted panel.
Anheim and his colleagues estimated that their gene panel approach cost $156 per patient, not including labor. They broke that down into a reagent cost of $70, a run cost of $68, and consumable item cost of $18. The amount of time needed to run the panel for a set of 24 patients varied between two to three days. By contrast, they estimated the whole-exome sequencing approach to cost between $850 and $1,113 per patient, before labor costs, and take between seven and 10 days for a series of six exomes.
"[T]his high-throughput sequencing strategy targeting 127 genes appears as a highly efficient, cost-effective diagnostic tool in the field of early-onset or familial movement disorders," they wrote.
The researchers noted, though, that targeted sequencing could be limited by the diagnostic lab's ability to incorporate newly identified genes into its test.