Study Supports Genetic Testing to Diagnose HAE of Unknown Cause

Use of genetic testing enabled the detection of hereditary angioedema (HAE) in a previously misdiagnosed woman, found to be carrying a gene variant linked with HAE of unknown genetic cause.

The findings support the consideration of genetic testing to diagnose unexplained angioedema, with an end goal of speeding treatment and improving outcomes.

The study, “Genotype-first analysis of a generally healthy population cohort supports genetic testing for diagnosis of hereditary angioedema of unknown cause,” appeared in the journal Allergy, Asthma & Clinical Immunology.

HAE is a rare genetic disorder characterized by sudden and recurrent episodes of swelling in the deeper layers of the skin, the upper airway, and the gastrointestinal tract.

The disease is divided into three types: type 1 and 2, caused by genetic mutations in the SERPING1 gene, and type 3, due to a mutation in the F12 gene. In HAE type 1, the genetic mutations lead to lower levels of C1-inhibitor (C1-INH), while in type 2, they cause a dysfunctional C1-INH whose levels remain normal. HAE type 3 is very rare, and is tied to the F12 gene, which codes for a blood clotting protein called coagulation factor XII.

Researchers note, however, that there are other forms of HAE, characterized by normal C1-INH and F12, for which the genetic cause is still unknown. These are described as HAE-U.

Given the disease’s severity and likelihood of underdiagnosis and misdiagnosis, researchers need to identify ways to diagnose the condition as early as possible.

Two new genes – PLG and ANGPT1 – recently have been proposed as the root cause of HAE-U. That led researchers at Inova Health System to investigate if genetic sequencing should be considered for diagnosing these patients.

The team tested blood samples of 2,820 adults without any genetic disorder to determine whether they carried either of the two proposed variants — one in the PLG gene, known as K330E, and the other in the ANGPT1 gene, called A119S.

The results revealed the K330E variant in a 31-year-old woman of European ancestry. No other variant in HAE-causing genes was found.

Subsequent review of the woman’s medical history revealed that she first began experiencing lip and tongue swelling at age 21. Her episodes had been occurring nearly once a year, and did not present with wheals — small, raised skin swellings that often are itchy. These episodes usually started in the morning and worsened throughout the day.

Though her tongue swelling had not caused respiratory distress, the patient sought treatment. She was given the allergy medication Benadryl (diphenhydramine, by Johnson & Johnson), steroids, and an EpiPen (epinephrine, by Mylan), intended for serious allergic reactions.

However, the woman’s episodes did not respond to treatment. Believing they were caused by an allergic reaction, the patient visited an allergist to determine the cause, but with no success. She had had no increased frequency of symptoms during her three pregnancies. Her sibling and parents had no reported episodes of angioedema. Yet genomic data was unavailable for these family members.

The scientists noted that, although HAE had not been suspected, the patient’s symptoms — swelling in the face without abdominal pain — were in line with those previously reported in people diagnosed with, or with family history of HAE who carried the K330E variant.

“The results support a role of PLG K330E in the pathogenesis of HAE and suggest that genetic testing be considered as an approach to diagnose patients with unexplained angioedema,” the researchers said.

They added that genetic testing “will facilitate selection of appropriate treatment, discontinuation of therapies ineffective for this condition, and timely diagnosis of affected family members.”