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  • Test code: 03373
  • Turnaround time:
    10–21 calendar days (14 days on average)
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  • Alternate specimens:
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  1. Neurology
  2. Invitae Periodic Paralysis Panel

Invitae Periodic Paralysis Panel

Test description

The Invitae Periodic Paralysis Panel analyzes three genes associated with periodic paralysis, a disorder characterized by temporary episodes of muscle weakness or paralysis. These genes were curated based on current evidence to provide a comprehensive test for the genetic causes of periodic paralysis.

Individuals with clinical signs and symptoms of periodic paralysis 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.

Genes tested

CACNA1S KCNJ2 SCN4A

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Primary panel (3 genes)

CACNA1S KCNJ2 SCN4A

Panel details and technical assay limitations

Clinical information

Periodic paralysis is a channelopathy characterized by episodes of muscle weakness. Periodic paralysis can be a primary condition or can occur as a feature of a larger syndrome. Primary periodic paralysis 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 periodic paralysis secondary to Andersen-Tawil syndrome, caused by mutations in the KCNJ2 gene, typically present with periodic paralysis together with ventricular arrhythmias and prolonged QT interval.

Proportion of cases attributed to variants in the listed genes
CACNA1S 60%
KCNJ2 60% of Andersen-Tawil syndrome
SCN4A 20%

This test does not include analysis of KCNJ18 which accounts for an estimated 3% of hypokalemic periodic paralysis.

Periodic paralysis associated with the CACNA1S, KCNJ2 and SCN4A genes is inherited in an autosomal dominant manner.

The penetrance of CACNA1S-related periodic paralysis is up to 90% in males and can be as low as 50% in females depending on the variant. Penetrance of SCN4A-related periodic paralysis 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 prevalence of periodic paralysis is estimated to occur in 1 out of every 100,000 individuals. Andersen-Tawil syndrome is diagnosed in less than 10% of periodic paralysis cases.

Periodic paralysis 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.

  1. Ackerman, MJ, Clapham, DE. Ion channels--basic science and clinical disease. N. Engl. J. Med. 1997; 336(22):1575-86. PMID: 9164815
  2. Chabrier, S, et al. Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene. J. Med. Genet. 2008; 45(10):686-8. PMID: 18835861
  3. Cheng, CJ, et al. Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. J. Biol. Chem. 2011; 286(31):27425-35. PMID: 21665951
  4. Ke, Q, et al. [The mutation R672H in SCN4A gene exists in Chinese patients with hypokalaemic periodic paralysis]. Zhonghua Yi Xue Za Zhi. 2006; 86(11):724-7. PMID: 16681942
  5. Matthews, E, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. 2009; 72(18):1544-7. doi: 10.1212/01.wnl.0000342387.65477.46. PMID: 19118277
  6. Miller, TM, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004; 63(9):1647-55. PMID: 15534250
  7. Sternberg, D, et al. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain. 2001; 124(Pt 6):1091-9. PMID: 11353725
  8. Vicart, S, et al. Hypokalemic Periodic Paralysis. 2002 Apr 30. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301512
  9. Zheng, J, et al. A novel Kir2.6 mutation associated with hypokalemic periodic paralysis. Clin Neurophysiol. 2016; 127(6):2503-8. PMID: 27178871

Assay and technical information

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.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CACNA1S NM_000069.2
KCNJ2 NM_000891.2
SCN4A NM_000334.4

Sponsored testing programs
Uncovering Periodic Paralysis
Clinical resources
Invitae brochure Neurology gene list
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. Ackerman, MJ, Clapham, DE. Ion channels--basic science and clinical disease. N. Engl. J. Med. 1997; 336(22):1575-86. PMID: 9164815
  2. Chabrier, S, et al. Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene. J. Med. Genet. 2008; 45(10):686-8. PMID: 18835861
  3. Cheng, CJ, et al. Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. J. Biol. Chem. 2011; 286(31):27425-35. PMID: 21665951
  4. Ke, Q, et al. [The mutation R672H in SCN4A gene exists in Chinese patients with hypokalaemic periodic paralysis]. Zhonghua Yi Xue Za Zhi. 2006; 86(11):724-7. PMID: 16681942
  5. Matthews, E, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. 2009; 72(18):1544-7. doi: 10.1212/01.wnl.0000342387.65477.46. PMID: 19118277
  6. Miller, TM, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004; 63(9):1647-55. PMID: 15534250
  7. Sternberg, D, et al. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain. 2001; 124(Pt 6):1091-9. PMID: 11353725
  8. Vicart, S, et al. Hypokalemic Periodic Paralysis. 2002 Apr 30. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301512
  9. Zheng, J, et al. A novel Kir2.6 mutation associated with hypokalemic periodic paralysis. Clin Neurophysiol. 2016; 127(6):2503-8. PMID: 27178871

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