Investigators Analyze the Current and Future Landscapes of Genetic Testing

Clinicians’ and researchers’ continuous expansion of genetic knowledge and the increasing availability of genetic testing carries the potential for exciting clinical impact in precision medicine. However, the volume and heterogeneous manifestations of autoinflammatory, autoimmune, and immunodeficient diseases can make it difficult for clinicians to identify who to test, the significance of genetic testing results, and the relevance of these results for patients.

Troy Torgerson, MD, PhD, Director of Experimental Immunology at the Allen Institute for Immunology and Affiliate Clinical Professor of Pediatrics at the University of Washington, and Ivona Aksentijevich, MD, Associated Investigator at the National Institutes of Health (NIH) National Human Research Genome Institute, shared insights on optimal genetic testing strategies as well as current challenges they hope to overcome in the future during the Monday, Nov. 18, session Genetic Testing in the Era of Inborn Errors of Immunity: Who to Test and How to Interpret.

According to Dr. Torgerson, there are a total of 560 defined inborn errors of immunity (IEI) disorders that are caused by 511 genes. Additionally, reduced penetrance and variable expressivity are common features of primary immune regulatory disorders (PIRDs), meaning only some individuals with a pathogenic variant in a gene develop features of a disorder, and individuals with the same genetic variant can express a range of symptoms.

With this variability, Dr. Torgerson shared several critical features that could signal a genetic immune disease. Genetic testing might be a logical next step if a patient is exhibiting symptoms of a disease at an unusually young age, or if a patient’s symptoms seem exceedingly severe or exhibit unusual infectious or autoimmunity characteristics. A family history of immune dysregulation can also serve as a key indicator.

“In seeing patients, you develop this sort of gut feeling about what’s off the rails and what isn’t,” he said. “I would just trust your gut because a lot of times it’s right.”

He also cited studies that indicate a correlation between genetic mutations or variants in pediatric patients with non-malignant lymphoproliferation or Evans syndrome.

When clinicians believe a genetic condition might be present and decide to initiate further analysis, Dr. Torgerson recommended beginning with broad-based genetic testing rather than relying on functional testing.

“Just go right to the genetics,” he said, explaining that because presentations can be highly variable, picking the right functional test can be a gamble.

Despite her agreement that genetic testing is critical in the differential diagnosis of primary immune disorders, Dr. Aksentijevich qualified that the diagnostic yield from whole-exome sequencing (WES) and whole-genome sequencing (WGS) for patients with IEIs is surprisingly low. Reviewing reports on molecular diagnostic yields published over the last five years, she found that the diagnostic yield from next-generation sequencing technologies like WES and WGS was no higher than 30%.

Dr. Aksentijevich cited the limitations of sequencing technologies, bioinformatics approaches, and the challenging task of searching for somatic mutations at a genome level as possible explanations for the low diagnostic yield of these tests. She added that periodic data reanalysis could lead to an increase in diagnostic yield.

Looking ahead, she identified outputs that could significantly improve the genetic testing landscape.

“There’s a need for high-throughput functional validations,” Dr. Aksentijevich said. “There’s a need also for trans-ancestral databases of germline, somatic, and copy number variants.”