Novel deep intronic variant in CLCN1 causing autosomal recessive myotonia congenita

Myotonia congenita is a skeletal muscle channelopathy caused by pathogenic variants in CLCN1, encoding the ClC-1 chloride channel. We report two sisters with clinical features consistent with recessive myotonia congenita and compound heterozygous variants in CLCN1 identified through short-read genome sequencing: a paternally inherited pathogenic missense variant c.871G > A (p.Glu291Lys) and a novel maternally inherited deep intronic variant, c.697-620 T > G. RNA sequencing of a muscle biopsy revealed that the deep intronic variant activates a cryptic splice donor site, resulting in 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, supporting degradation of the maternally-derived transcript. These findings confirm the likely pathogenicity of c.697-620 T > G as a novel loss-of-function variant in CLCN1 and expand the spectrum of CLCN1-related autosomal recessive myotonia congenita.