Myotonia congenita is a disorder in which muscles fail to relax properly after contraction. Patients experience stiffness, particularly after periods of rest, that can make simple movements — opening a door, shaking hands, climbing stairs — feel like a battle against their own bodies. The condition arises from defects in the CLCN1 gene, which encodes a chloride channel called ClC-1 found in skeletal muscle membranes. This channel is essential for regulating the electrical excitability of muscle fibers. When chloride ions cannot flow properly through the channel, muscle fibers become hyperexcitable, firing repetitive action potentials that produce the characteristic stiffness. The CLCN1 gene can be inherited in both dominant and recessive patterns, with recessive cases typically producing more severe symptoms. In the Iranian family studied, the index patient presented with severe myotonia that had a significant impact on daily life, consistent with the more severe end of the myotonia congenita spectrum.

Centronuclear myopathy, by contrast, is a structural muscle disease. The autosomal dominant form (ADCNM) is caused by variants in the DNM2 gene, which encodes dynamin-2, a large GTPase enzyme involved in membrane trafficking, vesicle formation, and the maintenance of muscle fiber architecture. In centronuclear myopathy, muscle fibers display centrally located nuclei — a feature normally seen only in embryonic muscle development — along with progressive weakness. The disease is fundamentally different from myotonia congenita: rather than a problem of electrical excitability, it is a problem of muscle fiber structure and maintenance. Patients with ADCNM typically experience progressive weakness rather than stiffness, and the condition can affect muscles throughout the body, sometimes including those involved in breathing and swallowing.

The Iranian family presented a clinical picture that overlapped both conditions. The index patient showed clinical and electrical myotonia — the hallmark of myotonia congenita — but also displayed myopathic changes on electromyography (EMG), the diagnostic technique that records electrical activity in muscles. Three affected brothers in the family showed myopathic features, suggesting that something beyond simple myotonia congenita was at play. This clinical ambiguity prompted the research team to perform whole-exome sequencing on the index patient, a technique that reads the protein-coding regions of the genome to identify disease-causing variants. The approach is particularly valuable in cases where the clinical picture does not point to a single gene, allowing researchers to scan thousands of genes simultaneously rather than testing one candidate at a time.

The genetic evaluation revealed a remarkable finding: two variants of the CLCN1 gene in a compound heterozygous state, meaning that the patient carried one variant on each copy of the gene. The first variant, c.1012 C > T (p.Arg338Ter), introduces a premature stop codon that truncates the chloride channel protein. The second, c.1355 C > T (p.Pro452Leu), substitutes a proline residue with leucine at position 452, a change that likely disrupts the protein’s structure and function. Compound heterozygosity for CLCN1 variants is consistent with autosomal recessive myotonia congenita, the more severe form of the disease. The finding explains the patient’s severe myotonia: with both copies of the CLCN1 gene compromised, the chloride channels in skeletal muscle membranes cannot function properly, producing the hyperexcitability that underlies the muscle stiffness. Sanger sequencing confirmed the variants, and co-segregation analyses within the family supported the recessive inheritance pattern.

But the story did not end there. In addition to the CLCN1 variants, the researchers identified a heterozygous variant in the DNM2 gene — c.2161G > A (p.Asp721Asn) — in three affected brothers with myopathic features. This variant substitutes an asparagine for an aspartic acid at position 721 of the dynamin-2 protein. Notably, the variant is classified as a variant of uncertain significance (VUS), meaning that its clinical impact cannot yet be determined with confidence. The classification reflects the fact that the variant has not been previously established as disease-causing, and its presence in affected individuals raises the possibility of its involvement in the accompanying myopathic phenotype. However, the researchers are careful to note that its contribution to the clinical manifestations remains uncertain and requires further investigation.

The co-existence of variants in two different neuromuscular disease genes within the same family is extraordinarily rare. Most patients with overlapping myotonia and myopathy carry variants in a single gene, or the overlap reflects the pleiotropic effects of one variant. The Iranian case suggests that the myopathic features in the affected brothers may be attributable to the DNM2 variant, while the severe myotonia stems from the compound heterozygous CLCN1 variants. This dual-hit model — two independent genetic defects producing two independent disease processes — offers a compelling explanation for a phenotype that would otherwise defy classification. The findings underscore the value of comprehensive genetic evaluation in patients with overlapping neuromuscular phenotypes, where a single-gene approach might miss the full genetic picture.

The technical details of the two genes illuminate why their co-existence produces such a distinctive clinical picture. The ClC-1 chloride channel is a voltage-gated channel that allows chloride ions to flow across the muscle membrane, stabilizing the resting potential and preventing repetitive firing. Variants that truncate the protein, such as p.Arg338Ter, typically produce non-functional channels through nonsense-mediated mRNA decay or misfolding. Missense variants, such as p.Pro452Leu, may disrupt the channel’s gating properties or its trafficking to the membrane. Dynamin-2, meanwhile, is a mechanochemical enzyme that assembles into helical polymers around membrane necks, catalyzing membrane fission during vesicle formation. In muscle fibers, dynamin-2 participates in the maintenance of the T-tubule system and nuclear positioning, and variants that alter its GTPase activity or its interactions with binding partners such as amphiphysin and BIN1 can produce the centronuclear architecture characteristic of ADCNM. The two proteins operate in entirely different cellular compartments and pathways, which explains why their co-existence produces a phenotype that combines electrical hyperexcitability with structural muscle disease.

The Iranian context adds another layer of significance to the finding. Consanguineous marriage remains relatively common in parts of Iran, increasing the likelihood of recessive disease within families. The recessive inheritance of myotonia congenita in this family is consistent with this demographic pattern, and the co-existence of a second neuromuscular variant within the same family highlights the diagnostic complexity that can arise in consanguineous populations. The researchers note that the family’s cooperation was essential to the study, and that written informed consent was obtained from all participants or their legal guardians. The study was approved by the Research Ethics Committee of Shahid Sadoughi University of Medical Sciences, and the datasets analyzed are not publicly available due to patient privacy and ethical restrictions.

The case offers a powerful lesson for the field of neuromuscular genetics. Patients with overlapping phenotypes — those whose symptoms do not fit a single disease category — may harbor variants in multiple genes, each contributing a distinct component of the clinical picture. Whole-exome sequencing, by scanning the entire coding genome simultaneously, allows researchers to identify such multi-gene co-existence that single-gene testing would miss. The Iranian family’s case demonstrates that the co-existence of myotonia and myopathy can reflect the co-existence of two independent genetic defects, each producing its own disease process. As genomic medicine becomes increasingly integrated into clinical practice, cases like this one will help clinicians understand that the human genome can produce clinical pictures far more complex than any single-gene model would suggest — and that comprehensive genetic evaluation remains the most powerful tool for unraveling them.

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

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

Article References: Haghighi, F. S., Kalantar, S. M., Ghasemi, N., Daneshipour, A., Mohammadi, S. A., Poorshekar, S., & Movahedinia, M. (2026). Co-existence of CLCN1 and DNM2 variants in a phenotype overlapping myotonia and myopathy. Molecular Biology Reports, 53(1), Article 1755. https://doi.org/10.1007/s11033-026-12805-8

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12805-8

Keywords: Co-existence, CLCN1, DNM2, variants, phenotype, overlapping, myotonia, myopathy, scientific research