PGmax^TM - Comprehensive Movement Disorders Panel

This panel includes genes in which sequencing variants and copy number variants have been associated with various types of pediatric- or adult-onset movement disorders. Movement disorders are a group of neurological disorders characterized by impaired or involuntary movements. Examples of movement disorders caused by genes in this panel include (but are not limited to) various types of ataxia, dystonia, parkinsonism, and tremor.

Genetic forms of ataxia are most often characterized by poor coordination of movement, a wide-based and unsteady gait, and poor coordination of the limbs and speech (also known as dysarthria; Bird. 2019. PubMed ID: 20301317). Autosomal dominant forms of ataxia (typically adult onset) are the most common form of hereditary ataxia with an estimated worldwide prevalence of 1-5 cases per 100,000 individuals. The most common forms are caused by repeat expansions; however, please note repeat expansion variants are not covered by this test. Autosomal recessive forms of ataxia (typically pediatric onset) have a prevalence of about 3 cases per 100,000 individuals (Bird. 2019. PubMed ID: 20301317).

Dystonia is characterized by excessive muscle contractions, resulting in abnormal, patterned movements such as twisting, repetitive motions, and abnormal postures. These patients may have tremors and experience exacerbation of dystonic posturing while attempting voluntary movements (Fuchs and Ozelius. 2013. PubMed ID: 24136457). In this way, it can be difficult to distinguish dystonia from ataxia in some patients. Dystonia is considered a common movement disorder amongst the general population: prevalence estimates for primary (isolated) dystonia have been reported to range from 10 to 37 cases per 100,000 individuals (Steeves et al. 2012. PubMed ID: 23114997).

Parkinsonism refers to a group of neurological abnormalities which includes tremor, bradykinesia (overall slowness of movement), and rigidity. These phenotypes are present in Parkinson’s disease (PD) as well as many other distinct disorders. PD is one of the most common movement disorders in the adult population, with an estimated incidence of 5 to 35 new cases per 100,000 individuals each year, and incidence significantly increases with age (Simon et al. 2020. PubMed ID: 31733690). Rare hereditary forms of PD and other disorders with parkinsonism can also occur in pediatric patients.

Essential tremor is one of the most common adult-onset neurologic disorders. Tremors are involuntary quivering movements that occur while performing voluntary movements, such as while moving a hand or arm (Clark and Louis. 2018. PubMed ID: 29325613).

Please note that abnormal movements that are only secondary to a primary phenotype (such as epilepsy, muscle weakness or muscle composition anomalies, or bone/joint abnormalities) are not considered movement disorders and therefore genes associated only with these phenotypes are not included in this test.

Genetic testing can aid in the differential diagnosis of movement disorders, which can be difficult to distinguish based on clinical features alone. One advantage of genetic testing is the possibility of being able to guide treatment decisions. Several types of movement disorders are caused by metabolic disturbances, and symptoms can be avoided or reduced by treatment with specific vitamin supplements or dietary modifications (Jinnah et al. 2018. PubMed ID: 28861905). Pharmaceutical intervention may be available for specific types of movement disorders as well. Diagnosis is also beneficial to patients with movement disorders so that they may identify support groups and organizations that provide support, additional resources, and a community of individuals and families with similar experiences.

The diverse collection of genes represented in this panel represent autosomal recessive, autosomal dominant, and X-linked movement disorders known to be caused by sequence variants and copy number variants. Both familial and sporadic forms of the various movement disorders covered by this test have been linked to a genetic etiology. The genes included in this panel encode proteins with a variety or biological functions, mostly affecting neuron function within the central and peripheral nervous systems. See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. Diagnostic rates for next generation sequencing in pediatric cerebellar ataxia testing have been reported to range from 25% to over 80%. By contrast, the diagnostic rate using next generation sequencing for adult-onset cerebellar ataxias caused by non-repeat expansion disorders was reported to be less than 10% (Krygier and Mazurkiewicz-Bełdzińska. 2021. PubMed ID: 34224032). The genes in this panel cover a broader range of phenotypes and thus the clinical sensitivity may vary from previous reports. We are currently unaware of any reports in the literature in which this specific group of genes have been sequenced together.

Analytic sensitivity for movement disorders caused by sequence variants or copy number variants is expected to be high because these types of pathogenic variants are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

The Comprehensive Movement Disorders Sequencing Panel is a phenotype-driven analysis and patient clinical information is required. This information can be submitted in the form of clinical notes or using our clinical phenotype checklist. For best results, we recommend including age of onset of symptoms, and if they are episodic, the frequency and duration of the episodes.

Reporting: Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype
• Variants in genes possibly associated with the provided phenotype

Of note, Next Generation Sequencing analysis of the SDHA gene is technically challenging due to the presence of segmental duplications and paralogy. Therefore, analysis of CNVs in this region is not included in this test.

Please note that the PGxome version of this test does not include testing for movement disorders caused by repeat expansions. Testing for individual repeat expansion disorders may be ordered in addition to the PGxome Comprehensive Movement Disorders Sequencing Panel at list price. 

If ordered on the PGnome platform, individuals will be screened for repeat expansions in ATXN2, C9orf72, FMR1, and PABPN1. For the repeat expansion screen, individuals with phenotypes consistent with disease in these genes will be evaluated for expansions. Our genome test screens for expanded allele repeat sizes with nearly 100% analytical specificity and sensitivity. Any potential expansions detected by the screening test will be confirmed with the appropriate confirmatory clinical repeat expansion test. Only those expansions that are confirmed will be reported.

Tests that meet our eligibility criteria for repeat expansion screening (described above) must have locus coverage of at least 20x for data to be considered reliable. This screen may not detect low-level mosaic expansions. Any potential expansions will be confirmed with an appropriate confirmatory repeat expansion test. Only results from the confirmatory repeat expansion test (including repeat count and methylation status, if applicable) will be included in the final report.

Variants in the mitochondrial genome will not be reported at this time.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).