Novel deep intronic variant in CLCN1 causing autosomal recessive myotonia congenita.

Deep intronic CLCN1 variant activating a cryptic splice donor site, with inclusion of an out-of-frame cryptic exon and partial nonsense-mediated decay: loss of function of the ClC-1 chloride channel.

Myotonia congenita is a skeletal muscle channelopathy caused by pathogenic variants in CLCN1, which encodes the ClC-1 chloride channel. The authors report two sisters with features consistent with recessive myotonia congenita and compound heterozygous CLCN1 variants identified by short-read genome sequencing: a paternally inherited pathogenic missense variant, c.871G>A (p.Glu291Lys), and a novel maternally inherited deep intronic variant, c.697-620T>G. RNA sequencing of a muscle biopsy showed that the deep intronic variant activates a cryptic splice donor site, leading to inclusion of an out-of-frame cryptic exon, multiple aberrant splice junctions and partial nonsense-mediated decay. Allele-specific expression analysis showed a 70:30 skew favouring the paternal allele, consistent with degradation of the maternal transcript, confirming the likely pathogenicity of c.697-620T>G as a loss-of-function variant.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a scenario regularly met in channelopathies: a single missense variant found against a clearly recessive phenotype, where one must resist concluding an atypical dominant form and instead look for the second allele deep in the introns. What the paper mainly shows is that short-read genome sequencing already saw the variant, but only RNA sequencing in the relevant tissue, here muscle, made it interpretable, with allele-specific expression providing the quantitative argument that splicing data often lack. Caution nonetheless: a single family, two sisters, and access to muscle biopsy that remains unrealistic outside neuromuscular networks.

Analysis by Dr Thibaut Benquey