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  1. Neurology
  2. Invitae Periodic Paralysis Panel

Invitae Periodic Paralysis Panel

Test description

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.

Genes tested

CACNA1S KCNJ2 RYR1 SCN4A

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Primary panel (4 genes)

CACNA1S KCNJ2 RYR1 SCN4A

Panel details and technical assay limitations

Clinical information

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
CACNA1S 60%
KCNJ2 60% of Andersen-Tawil syndrome
SCN4A 20%
RYR1 unknown

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.

  1. Miller, TM, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004; 63(9):1647-55. PMID: 15534250
  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. 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
  4. Ackerman, MJ, Clapham, DE. Ion channels--basic science and clinical disease. N. Engl. J. Med. 1997; 336(22):1575-86. PMID: 9164815
  5. Zheng, J, et al. A novel Kir2.6 mutation associated with hypokalemic periodic paralysis. Clin Neurophysiol. 2016; 127(6):2503-8. PMID: 27178871
  6. 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
  7. Vicart, S, et al. Hypokalemic Periodic Paralysis. 2002 Apr 30. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301512
  8. 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
  9. 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
  10. Marchant, CL, et al. Mutation analysis of two patients with hypokalemic periodic paralysis and suspected malignant hyperthermia. Muscle Nerve. 2004 Jul; 30(1):114-7. PMID: 15221887
  11. Zhou, H, et al. Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2010 Mar; 20(3):166-73. PMID: 20080402
  12. Matthews, E, et al. Atypical periodic paralysis and myalgia: A novel RYR1 phenotype. Neurology. 2018 Jan 30; 90(5):e412-e418. PMID: 29298851

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.

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
CACNA1S NM_000069.2
KCNJ2 NM_000891.2
RYR1 NM_000540.2
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. Marchant, CL, et al. Mutation analysis of two patients with hypokalemic periodic paralysis and suspected malignant hyperthermia. Muscle Nerve. 2004 Jul; 30(1):114-7. PMID: 15221887
  6. Matthews, E, et al. Atypical periodic paralysis and myalgia: A novel RYR1 phenotype. Neurology. 2018 Jan 30; 90(5):e412-e418. PMID: 29298851
  7. 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
  8. Miller, TM, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004; 63(9):1647-55. PMID: 15534250
  9. 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
  10. Vicart, S, et al. Hypokalemic Periodic Paralysis. 2002 Apr 30. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301512
  11. Zheng, J, et al. A novel Kir2.6 mutation associated with hypokalemic periodic paralysis. Clin Neurophysiol. 2016; 127(6):2503-8. PMID: 27178871
  12. Zhou, H, et al. Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2010 Mar; 20(3):166-73. PMID: 20080402

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