A new, highly sensitive genetic test that screens the entire SERPING1 gene is better than conventional genetic testing for diagnosing type 1 and type 2 hereditary angioedema, new research shows.
Researchers now recommend this test as the first-line or as a confirmatory method for the genetic diagnosis of these patients.
The study, “Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency,” was published in the journal Gene.
Hereditary angioedema is a rare genetic disorder that causes swelling of the skin and tissue beneath the skin. In type 1, the disease is caused by low levels of the C1 inhibitor protein, and in type 2, by the production of a faulty protein. Type 3 results from mutations in the coagulation factor XII.
Researchers have reported more than 450 mutations in the SERPING1 gene, which provides instructions for making the C1 inhibitor protein.
Genetic testing of subjects suspected of having angioedema is important not only for clinical practice but also for research.
But conventional tests are cumbersome, time-demanding, and not sensitive enough to identify all cases. In a small proportion of patients (approximately 5-10%), no SERPING1 mutations can be detected even after thorough analysis.
Part of the problem is that standard tests do not cover the entire SERPING1 gene, skipping regions that are not translated into proteins, but that can harbor mutations that lead to angioedema.
Taking advantage of a powerful technology called next-generation sequencing, researchers developed a new genetic test that, for the first time, is able to cover the entire SERPING1 gene.
Researchers validated the new test using 102 DNA samples previously typed with conventional methods, as well as 115 negative controls, and 95 randomly selected DNA samples from affected family members of patients.
In total, 135 different angioedema-associated SERPING1 variants were used to validate the new test, which was able to detect all but two of these cases.
Since it can screen the entire SERPING1 gene, the test is able to correctly identify mutations otherwise missed by conventional approaches.
In samples from 91 patients already diagnosed but not genotyped yet, the new test was able to detect SERPING1 mutations or their absence, as well as the standard screens, in all cases.
It was also able to identify 15 new mutations that had not been previously reported.
Overall, the new approach provides very high sensitivity (98.96%), specificity (100%), and accuracy (99.35%).
Two important measures of test error, the false negative rate — the frequency of positive cases incorrectly typed as negative — and the false positive rate — the proportion of negative cases misidentified as positive — were very low or close to zero.
The new method’s performance “recommends its implementation as a first line approach for the genetic testing of C1-INH-HAE patients or as a confirmatory method,” the researchers wrote.