Rare MYOF Genetic Variant Linked to Angioedema With Normal C1-INH Levels

A rare genetic variant in the MYOF gene may explain why a 51-year-old woman suffered from recurring angioedema attacks for 13 years despite having normal C1-esterase inhibitor levels, according to a case report published in the Annals of Allergy, Asthma & Immunology.

The discovery, detailed in a study titled “Bradykinin-Mediated Angioedema with Normal C1 Inhibitor Associated with a MYOF Variant: Therapeutic and Structural Insights,” offers a potential answer for a subset of patients whose swelling episodes defy standard diagnostic markers. For over a decade, the woman experienced sudden, painful swelling in her face, arms, legs, and genital area, with episodes lasting two to three days at a time.

While most cases of hereditary angioedema (HAE) are tied to low levels or dysfunction of the C1-INH protein, this patient presented with entirely normal protein levels and activity. This misalignment suggested her condition was driven by bradykinin—a molecule that triggers swelling by making blood vessels leakier—rather than a deficiency in the protein meant to regulate it.

Angioedema News reported that the woman’s symptoms persisted even after she tried antihistamines, corticosteroids, and the asthma medication omalizumab. Because her swelling did not respond to these treatments, medical teams concluded that histamine was likely not the culprit, pointing them back toward the bradykinin pathway.

To find the source of the dysfunction, researchers turned to genetic testing. While they found no known disease-causing mutations in typical angioedema genes, they identified a rare N267D variant in the MYOF gene, which provides instructions for making myoferlin, a protein essential to blood vessel function.

The researchers suspect this variant might make blood vessels unusually sensitive to bradykinin. Although the variant was also found in several of her relatives who showed no symptoms, computer-based modeling suggested the mutation could alter how myoferlin interacts with cell membranes. This could disrupt how endothelial cells—the cells lining the inside of blood vessels—recycle certain receptors, potentially allowing fluid to escape into tissues more easily.

The woman showed signs of new blood vessel growth and fewer tiny vessels around her fingernails, abnormalities previously seen in other HAE patients carrying MYOF variants. Her blood levels of VEGF-A, a protein involved in blood vessel growth, were also higher than those measured in healthy individuals.

Year	Treatment Type	Outcome
2021	Therapeutic plasma exchange (TPE)	Episodes decreased from several per month to one every one or two months.
2025 (February)	Weekly C1-INH concentrate infusions	Swelling stopped completely during treatment but returned two weeks after stopping.
2025 (December)	Orladeyo (berotralstat)	Patient remained free of swelling attacks over eight months of follow-up.

The use of therapeutic plasma exchange in 2021 was based on existing reports of its success in treating severe angioedema with normal C1-INH levels. While it provided relief, the treatment was eventually discontinued after three years due to catheter-related issues. Later, in December 2025, the oral medication Orladeyo—which blocks the enzyme responsible for producing bradykinin—successfully halted her attacks for at least eight months.

The case highlights the complexity of diagnosing “type 3” HAE, a form where C1-INH levels remain normal. While researchers have linked several other genes to this form, the specific roles of those variants remain poorly understood. The researchers said that “functional studies are now required to determine whether this variant directly alters myoferlin-dependent membrane trafficking and endothelial barrier regulation.”

“This case integrates converging clinical, therapeutic, vascular, genetic, and structural evidence supporting a bradykinin-mediated endothelial disorder,” the researchers wrote.

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