Co-existence of CLCN1 and DNM2 variants in a phenotype overlapping myotonia and myopathy

Myotonia congenita (MC) is characterized by impaired muscle relaxation following contraction. Autosomal dominant centronuclear myopathy (ADCNM) is characterized by centrally located nuclei and muscle weakness. We aimed to identify potential pathogenic variants responsible for a phenotype overlapping severe myotonia and myopathy in an Iranian family.

We performed whole-exome sequencing on an index patient with clinical/electrical myotonia and myopathic changes on electromyography (EMG). We confirmed candidate genes by Sanger sequencing and performed co-segregation analyses.

Genetic evaluation revealed two variants of NM_000083.3(CLCN1):c.1012 C > T (p.Arg338Ter) and NM_000083.3(CLCN1):c.1355 C > T (p.Pro452Leu) of the CLCN1 gene in a compound heterozygous state, consistent with recessive myotonia congenita. In addition, a heterozygous NM_001005361.3(DNM2):c.2161G > A (p.Asp721Asn) variant of uncertain significance (VUS) was identified in three affected brothers with myopathic features.

This study is a rare report of the co-existence of myotonia myopathy in an Iranian family. The findings support an autosomal recessive inheritance of myotonia congenita associated with the compound heterozygous CLCN1 variants. The co-occurring DNM2 p.Asp721Asn variant of uncertain significance (VUS) in affected individuals raises the possibility of its involvement in the accompanying myopathic phenotype; however, its contribution to the clinical manifestations remains uncertain and requires further investigation. These findings underscore the value of comprehensive genetic evaluation in patients with overlapping neuromuscular phenotypes.