The Invitae Periodic Paralysis Panel analyzes four genes associated with hypokalemic periodic paralysis (HOKPP), which is a disorder characterized by muscle weakness or paralysis with low serum potassium. These genes were curated based on current evidence to provide a comprehensive test for the genetic causes of hypokalemic periodic paralysis.
Individuals with clinical signs and symptoms of HOKPP may benefit from diagnostic genetic testing to confirm the diagnosis, provide anticipatory guidance, help determine which relatives are at risk, or guide possible enrollment in clinical trials.
CACNA1S KCNJ2 RYR1 SCN4A
CACNA1S KCNJ2 RYR1 SCN4A
Hypokalemic periodic paralysis (HOKPP) is a channelopathy characterized by episodes of muscle weakness accompanied by a low level of serum potassium. HOKPP can be a primary condition or can occur as a feature of a larger syndrome. Primary HOKPP is associated with the CACNA1S and SCN4A genes. Frequency, duration and severity of the episodes are highly variable across affected individuals. Age of onset of first episode can be as early as the first year of life, or as late as 20 years of age. Symptoms improve with potassium intake. Myopathy, which can be mild or severe, develops in about 25% of affected individuals and occurs at variable ages. Individuals with HOKPP secondary to Andersen-Tawil syndrome, caused by mutations in the KCNJ2 gene, typically present with HOKPP together with ventricular arrhythmias and prolonged QT interval. Studies have also identified RYR1 variants in individuals with periodic paralysis. Often described as “atypical” periodic paralysis, individuals experienced the onset of episodic muscle paralysis beginning in early adulthood with or without congenital myopathy.
|Proportion of cases attributed to variants in the listed genes|
|KCNJ2||60% of Andersen-Tawil syndrome|
This test does not include analysis of KCNJ18 which accounts for an estimated 3% of hypokalemic periodic paralysis.
HOKPP associated with the CACNA1S, KCNJ2 and SCN4A genes is inherited in an autosomal dominant manner. The RYR1 gene is associated with both autosomal recessive and dominant forms of periodic paralysis.
The penetrance of CACNA1S-related HOKPP is up to 90% in males and can be as low as 50% in females depending on the variant. Penetrance of SCN4A-related HOKPP appears to be variant dependent; complete penetrance has been observed for certain variants, however in females, low penetrance has been observed for other variants. Andersen-Tawil syndrome demonstrates reduced penetrance and variable expressivity. The penetrance of RYR1-related periodic paralysis is unknown.
The prevalence of HOKPP is estimated to occur in 1 out of every 100,000 individuals. Andersen-Tawil syndrome is diagnosed in less than 10% of HOKPP cases.
HOKPP is a clinically heterogeneous group of disorders. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform family planning.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|