Genetic testing advances help to uncover primary immune deficiency diseases

Infections caused by primary immunodeficiency diseases (PID) can be persistent and life-threatening. More than 450 PIDs have been identified, yet diagnosing them quickly and accurately remains a difficulty. Investigators employed next-generation sequencing technology to evaluate a DNA panel of 130 distinct immune system genes from 22 study participants in a new study published in Elsevier’s The Journal of Molecular Diagnostics.

Researchers discovered that many of the patients had inherited a genetic abnormality that produced an immune system disorder. These discoveries will help members of the family who may have inherited the same genetic defect have better treatment options and receive an earlier diagnosis.

Genetic testing was costly to perform and was mostly targeted to DNA sequencing of a single or very small number of genes. Therefore, a genetic diagnosis was limited for many patients with PIDs.”

Dr Lloyd J. D’Orsogna, MBBS & PhD, Study Lead Investigator, School of Medicine, University of Western Australia

D’Orsogna is also worked in Fiona Stanley Hospital, Perth, Western Australia, Department of Clinical Immunology, PathWest Laboratory Medicine.

Recent advances in genetic technology allow affordable testing of multiple genes from the same individual. We can therefore identify a specific gene that may lead to frequent infections in patients. An earlier and more accurate diagnosis may improve the patient outcome and prevent complications.”

Dr Lloyd J. D’Orsogna, MBBS & PhD, Study Lead Investigator, School of Medicine, University of Western Australia

The study included 22 unrelated individuals with common variable immunodeficiency (CVID), a common variety of PID, and a previously unknown genetic diagnosis. A next-generation sequencing panel encompassing 120 distinct immune genes was used to examine and analyze DNA samples.

A total of 130 genetic variations were discovered and analyzed. Literature reviews, functional tests, and family studies were used to determine the pathogenicity of new mutations not previously related to CVID.

Six of the 22 patients had likely pathogenetic variations found by the researchers (27%). Variants of unknown significance (VOUS) were discovered in four more cases. VOUS are genetic variations with unknown clinical relevance but the potential to cause disease. In all, roughly half of the patients had genetic abnormalities, according to the researchers. Sanger sequencing was used to confirm all of the identified variations.

A patient with a previously unreported new mutation in the AICDA gene was one of the study’s outstanding discoveries. D’Orsogna’s kid was likewise diagnosed with CVID and inherited the same mutation as D’Orsogna. Another patient had a unique pathogenic variation of the ICOS gene, which has been linked to immunodeficiency and immunological dysfunction.

A genetic mutation in the BAFF-R gene, which improves B cell survival, was also discovered in another CVID patient; however, flow cytometry analysis proved that it was harmful.

Patients’ focused therapy options can be informed by genetic diagnostics. They can also help family members of patients with confirmed CVID get help sooner. Before beginning a family, the son of the patient with the unique AICDA mutation was sent for genetic counseling.

I hope the new age of genetic medicine enables earlier and more accurate diagnosis, likely leading to better treatment and outcomes for all.”

Dr Lloyd J. D’Orsogna, MBBS & PhD, Study Lead Investigator, School of Medicine, University of Western Australia