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  • Test code: 03375
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Myotonia and Paramyotonia Congenita Panel

Test description

The Invitae Myotonia and Paramyotonia Congenita panel analyzes 2 genes associated with non-dystrophic forms of myotonia. These genes were curated based on the available evidence to date to provide a comprehensive test for myotonia and paramyotonia congenita.

Individuals with clinical signs and symptoms of myotonic syndromes may benefit from diagnostic genetic testing to confirm the diagnosis, provide anticipatory guidance, help determine which relatives are at risk, and/or guide enrollment in certain clinical trials. Because these conditions have multiple inheritance patterns and variable phenotypes, it is particularly helpful if the inheritance pattern or disease presentation is unclear.

This test does not include DMPK or CNBP, the genes that cause myotonic dystrophy types 1 and 2.

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Primary panel (2 genes)

CLCN1 SCN4A

Alternative tests to consider

For a broader analysis of the genetics of neuromuscular disorders:

Myotonia congenita and paramyotonia congenita are skeletal muscle disorders characterized by muscle stiffness that is not accompanied by muscle wasting. In myotonia congenita, stiffness is most severe when movements are initiated, but may improve on repetition (the “warm-up” phenomenon). In paramyotonia congenita, stiffness does not improve but rather worsens with repetition. Both conditions may be exacerbated by cold temperatures, although this is more pronounced in individuals with paramyotonia congenita. These conditions may also be associated with intermittent or permanent mild to severe muscle weakness, and respiratory distress has been reported in some individuals. Both myotonia and paramyotonia congenita show variable clinical severity between and within families.

CLCN1 and SCN4A are the only known genetic causes of myotonia congenita and paramyotonia congenita, respectively. In individuals affected with non-dystrophic myotonia, analysis of both of these genes has been shown to have a very high diagnostic yield (>90%).

CLCN1-related myotonia congenita may be inherited in an autosomal dominant or autosomal recessive pattern. Autosomal dominant myotonia congenita is known as Thomsen disease and autosomal recessive myotonia congenita is known as Becker disease. SCN4A-related paramyotonia congenita is inherited in an autosomal dominant pattern.

Autosomal dominant myotonia congenita is known to have reduced penetrance and variable severity within families. Autosomal recessive myotonia congenita, in contrast, is highly penetrant, as is paramyotonia congenita.

Myotonia congenita has an estimated prevalence of 1 in 100,000 individuals worldwide. Due to founder effects, the prevalence of myotonia congenita in Scandinavia is elevated to 1 in 10,000. Paramyotonia congenita is more rare, with an estimated prevalence of less than 1 in 100,000 individuals worldwide.

This test is appropriate for individuals with a clinical suspicion of non-dystrophic myotonia.

  1. Brugnoni, R, et al. A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. J. Hum. Genet. 2013; 58(9):581-7. PMID: 23739125
  2. Heatwole, CR, et al. The diagnosis and treatment of myotonic disorders. Muscle Nerve. 2013; 47(5):632-48. PMID: 23536309
  3. Imbrici, P, et al. ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation. J. Physiol. (Lond.). 2015; 593(18):4181-99. PMID: 26096614
  4. Lossin, C, George, AL. Myotonia congenita. Adv. Genet. 2008; 63:25-55. PMID: 19185184
  5. Miller, TM, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004; 63(9):1647-55. PMID: 15534250
  6. Miller, TM. Differential diagnosis of myotonic disorders. Muscle Nerve. 2008; 37(3):293-9. PMID: 18067134
  7. Parasivam, S, et al. Clinical, electrophysiological and genetic features of a large Australian family with paramyotonia congenita. Med. J. Aust. 2009; 190(6):334-6. PMID: 19296818
  8. Raja, Rayan, DL, et al. A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1. Neurology. 2012; 78(24):1953-8. PMID: 22649220
  9. Richardson, RC, et al. Truncating CLCN1 mutations in myotonia congenita: variable patterns of inheritance. Muscle Nerve. 2014; 49(4):593-600. PMID: 23893571
  10. Trip, J, et al. In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia. Eur. J. Hum. Genet. 2008; 16(8):921-9. PMID: 18337730
  11. Trivedi, JR, et al. Nondystrophic myotonia: challenges and future directions. Exp. Neurol. 2014; 253:28-30. PMID: 24361411

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

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
CLCN1 NM_000083.2
SCN4A NM_000334.4