Myotonia Congenita via the CLCN1 Gene

Myotonia congenita (MC) is characterized by muscle stiffness in the legs, arms, and sometimes in the face, eyelids and tongue (Lossin et al. 2008). The muscle stiffness can be alleviated by brief exercise (known as the “warm-up” phenomenon). This is different from paramyotonia, a disease manifesting worse stiffness after exercise. Most patients with MC have hypertrophic muscles. The severity of the clinical symptoms is associated with the inheritance mode of the disease. In general, patients with autosomal recessive form of MC may have more severe symptoms.The onset of symptoms is variable, usually in infancy or childhood with some rare cases where onset may be as late as in patients’ 30s or 40s.

Patients with MC may be at an increased risk for adverse anesthesia-related events, therefore anesthesia should be used with caution (Bandschapp et al. 2013).

MC can be inherited in an autosomal dominant (AD, also known as Thomsen disease) or autosomal recessive (AR, also known as Becker disease) manner (Dunø et al. 2005). Cases of semi-dominant inheritance, i.e., a homozygote manifests more severe phenotypes than a heterozygote, have also been reported (Kuo et al. 2006; Lin et al. 2006).

Myotonia congenita is caused by pathogenic variants in CLCN1 (Abdalla et al. 1992). The CLCN1 gene encodes the voltage-gated chloride channel ClC-1, which is highly expressed in the sarcolemma in skeletal muscle. The main function of ClC-1 is to regulate cellular excitability and to stabilize the resting potential (Pedersen et al. 2016). Pathogenic variants in CLCN1 gene can cause muscle fibers to show abnormally exaggerated response to stimulation. To date, over 260 different pathogenic variants have been identified, and more than 70% of them are missense or nonsense (Human Gene Mutation Database). The majority of the CLCN1 variants are associated with AR myotonia, whereas some variants have been found in both AD and AR form of the disease (Dunø et al. 2005). Pathogenic variants associated with dominant myotonia are mainly located in exon 8 (Fialho et al. 2007).

The clinical sensitivity of this test is expected to be high, because CLCN1 is the only known causative gene for classical myotonia congenita. More than 95% of pathogenic variants causing myotonia congenita (both autosomal dominant and recessive) can be detected by this test (Dunø et al. 2005).

This test provides full coverage of all coding exons of the CLCN1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).