Primary immunodeficiency disorders, or PIDs, often arise from genetic abnormalities. They can cause chronic infections or series of infections that go on for a lifetime. Proper diagnosis is important for determining treatment, prognosis, and other related aspects of a PID patient’s condition. Next generation sequencing is one of the latest methods for obtaining the needed diagnosis.
In a recent study reported in ScienceDaily, researchers used next generation sequencing to test 130 different immune system genes. The genetic samples were donated by 22 study participants. Results showed that many of these people had inherited a genetic defect that resulted in an immune system disorder.
Several benefits arise from being able to determine the genetic status of those who suffer from PIDs. Earlier diagnosis and better treatments are some of the main benefits for the patient, but that isn’t all. Family members who may have inherited the same anomalies can be detected and treated early as well, potentially preventing serious complications that would arise from waiting.
How Next-Generation Sequencing Surpasses Prior Testing Methods
Before the arrival of next generation sequencing, genetic testing was both expensive and limited. In many cases, only a single gene was tested for, or at most, a few genes. This made it easy to miss genetic causes of PIDs, since a problem with an untested gene would go undetected.
With next-generation sequencing, it is possible to affordably test a wide range of genes. It is also possible to spot and study variations in quantities not previously feasible. For example, in the latest test of 120 genes, over 130 variants were discovered. These variants were then studied for pathogenicity based on literature review, family studies, and functional assays. This provides a much clearer roadmap for determining which variants are problematic and what should be done about those that cause issues.
Six of the 22 patients in this study were found to have variants known to be pathogenic. Another four had variants of unknown significance (VOUS). All of the detected variants were then confirmed with the standard, older, Sanger sequencing method. When these patient results are added together, that is almost half of the patients who were found to have genetic abnormalities involving the studied immune system genes.
In one patient, next-generation sequencing found a novel gene variant that had not yet been reported. Her son was found to have inherited the same mutation, and has a confirmed diagnosis of CVID (common variable immunodeficiency). Another patient was found to have a variation in the BAFF-R gene. While this would normally enhance B-cell survival, flow cytometry analysis confirmed that the variant is pathogenic. Other gene-specific findings were also made.
With genetic diagnoses like these, it is possible to develop targeted therapeutic options that were not possible or feasible beforehand. Family members of those with confirmed CVID can also benefit from earlier interventions. Such interventions can range from early treatment for disease that they develop all the way to genetic counseling prior to starting their own families.
The study’s lead investigator, Dr. Lloyd J. D’Orsogna of the University of Western Australia, was heartened by the results. He holds high hopes that next generation sequencing will bring about earlier, more accurate diagnosis – and as a result, better treatments and outcomes for all involved.