Why the study?
Patients with concomitant mutations in CLCN1 and SCN4A manifest different unique symptoms from mutations in either gene alone, but clinical descriptions remain rare.
The identification of a novel CLCN1 F306S mutation coexisting with an SCN4A mutation expands the genetic database for myotonia congenita and highlights the value of whole-exome sequencing in atypical myotonic patients.
Digenic CLCN1/SCN4A mutations may underlie atypical myotonia-paralysis; extends phenotypic spectrum but remains hypothesis-generating pending larger studies.
Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Nav1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.
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Zhao et al. (2020) studied this question.
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