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.
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.
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|