New Genetic Test Enables Earlier, More Accurate Diagnosis of Primary Immunodeficiency Disorders

Primary immunodeficiency disorders (PID) can lead to chronic and sometimes fatal infections. Over 450 PIDs have been described, but rapid and accurate diagnoses remain a challenge. In a new study in The Journal of Molecular Diagnostics, published by Elsevier, the researchers used next-generation sequencing technology to test a DNA panel of 130 different immune system genes from 22 study participants. They discovered that many patients had inherited a genetic defect that caused a disorder in their immune system. These findings will facilitate better treatment options and earlier diagnosis in family members who may have inherited the same genetic abnormality.

Genetic testing was expensive to perform and primarily aimed at DNA sequencing of a single or very small number of genes. Therefore, a genetic diagnosis was limited for many patients with PID.”

Lloyd J. D’Orsogna, MBBS, PhD, Principal Investigator, School of Medicine, University of Western Australia; and Department of Clinical Immunology at PathWest Laboratory Medicine, Fiona Stanley Hospital, Perth, Western Australia

“Recent advances in genetic technology make it possible to test several genes from the same individual inexpensively. We can therefore identify a specific gene that may lead to frequent infections in patients. Earlier and more accurate diagnosis can improve patient outcomes and prevent complications,” said Dr. D’Orsogna.

Twenty-two unrelated patients with common variable immunodeficiency (CVID), a common type of PID and a previously unknown genetic diagnosis, were recruited for the study. DNA samples were tested and processed with a next-generation sequencing panel containing 120 different immune genes. One hundred and thirty genetic variants have been identified for analysis. The pathogenicity of new variants not previously associated with CVID was assessed by literature review, functional testing, and familial studies.

Investigators identified probable pathogenic variants in six of 22 patients (27%). In four other patients, variants of unknown significance (YOU) were identified. YOU are genetic variants whose clinical significance is unclear at this stage but which could be the cause of the disease. Overall, investigators were able to identify genetic abnormalities in nearly half of the patients. All detected variants were confirmed by conventional Sanger sequencing.

Among the study’s notable findings was a patient with a new variant of AICDA gene that had not been previously reported. Her son also had a confirmed diagnosis of CVID and also inherited the same mutation. Another patient had a novel pathogenic variant of SICO gene involved in immunodeficiency and immune response. In another CVID patient, a genetic variant was also detected in the BAFF-R gene, which improves B cell survival; however, it was confirmed as a pathogen by flow cytometry analysis.

These genetic diagnoses can inform decisions about targeted treatment options for patients. They can also provide earlier intervention for family members of patients with confirmed CVID. For example, the son of the patient with the novel AICDA variant was referred for genetic counseling before starting a family.

“I hope the new era of genetic medicine will allow for earlier and more accurate diagnosis, likely leading to better treatments and outcomes for everyone,” Dr. D’Orsogna said.


Journal reference:

Kermode, W. et al. (2022) A new amplicon-targeted next-generation sequencing gene panel for the diagnosis of common variable immunodeficiency has high diagnostic yield: results from the Perth CVID Cohort Study. Journal of Molecular Diagnostics.

Irene B. Bowles