Abstract - 2018 - Research and Practice in Thrombosis and Haemostasis
Genetic Test Can Diagnose Certain Immune System Disorders
Primary immunodeficiency disorders (PID) can result in chronic and sometimes life-threatening infections. More than 450 PIDs have been described, but timely and accurate diagnoses remain a challenge. In a new study in The Journal of Molecular Diagnostics, published by Elsevier, investigators used next-generation sequencing technology to test a DNA panel of 130 different immune system genes from 22 study participants. They found 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 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," explained lead investigator Lloyd J. D'Orsogna, MBBS, PhD, School of Medicine, the University of Western Australia; and Department of Clinical Immunology at PathWest Laboratory Medicine, Fiona Stanley Hospital, Perth, Western Australia.
"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. 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 were identified for analysis. The pathogenicity of the novel variants not previously associated with CVID were assessed through literature review, functional assays, and family studies.
The investigators identified likely pathogenetic variants in six of the 22 patients (27%). In an additional four patients, variants of unknown significance (VOUS) were identified. VOUS are genetic variants whose clinical significance is not clear at this stage but might cause the disease. Overall, the investigators were able to identify genetic abnormalities in nearly half of the patients. All detected variants were confirmed with conventional Sanger sequencing.
Among the notable findings of the study was a patient with a novel variant in the AICDA gene that had not previously been reported. Her son also had a confirmed diagnosis of CVID and has also inherited the same mutation. Another patient had a novel pathogenic variant of the ICOS gene, which is implicated in immunodeficiency and immune response. In another CVID patient, a genetic variant was also detected in the BAFF-R gene, which enhances B cell survival; however, it was confirmed as pathogenic by flow cytometry analysis.
Such genetic diagnoses can inform decisions on targeted therapeutic 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 age of genetic medicine enables earlier and more accurate diagnosis, likely leading to better treatment and outcomes for all," said Dr. D'Orsogna.
Insights Into Causes Of Rare Genetic Immune Disorders
The cellular glitches underlying a rare genetic disorder called activated PI3K Delta syndrome 2 (APDS2) have been identified by researchers at the Garvan Institute of Medical Research. The disorder is caused by genetic variations that disrupt immune cell signalling through a protein called PI3K.
"This study tells us how signalling in the immune system needs to be tightly balanced to make an effective response to infection. Sometimes it's turned down and you have a problem, and sometimes signalling being turned up can interfere with an immune response," says Associate Professor Elissa Deenick, Head of the Lymphocyte Signalling and Activation Lab, co-Lead of the Precision Immunology Program at Garvan and senior author of the paper.
PI3K plays a crucial role in activating immune cells for growth, proliferation, survival, migration and function. The researchers found that the genetic variations in APDS2 and a similar disorder, APDS1, alter PI3K signalling in different ways, leading to distinct effects on the immune system.
The APDS disorders are similar in their impacts but follow different genetic pathways. Variations in the PIK3R1 gene underlie APDS2, while variations in PIK3CD underlie APDS1. Though both result in increased PI3K signalling, their subtle differences -- in specific cells, timescales, and mechanisms -- yield distinct immune effects. In APDS2, fewer responding B cells are generated in response to vaccination, whereas in APDS1, the number of T cells is reduced. But in both cases, the disorders result in poor antibody responses. In addition, APDS2 variations appear to affect non-immune cells, resulting in growth delays.
These results also tell us about the signals that are required to achieve good vaccine responses in general. "Even for people who don't have these two rare genetic conditions, other genes can impact these pathways -- which could contribute to why different people have varied responses to vaccinations," says Dr Tina Nguyen, co-lead author of the study and Research Officer at Garvan.
The findings reveal how finely tuned immune cell signalling must be, and how even minor disruptions can lead to immune deficiency or dysfunction. They are a significant step towards understanding the molecular processes and developing more targeted and effective treatments for the disorders.
"People with mysterious conditions often face challenges in obtaining an accurate diagnosis and understanding the root causes of their health issues. With better access to genomic testing, it's going to become much easier for patients to receive diagnoses for conditions like APDS2. Knowing the genetic basis of a disease can enable targeted, personalised treatment plans that give patients the best chance of effective management or, hopefully over time, a cure," says Professor Stuart Tangye, a senior investigator of the paper and Head of the Immunobiology and Immunodeficiency Lab at Garvan.
Genetic Variant Protects Against Rash Of Autoimmune Diseases
Tweaking activity of one protein may help protect against 10 autoimmune diseases, a new study suggests. The protein, tyrosine kinase 2 or TYK2, helps regulate how strongly the immune system responds to threats.
Using genetic data from more than 36,000 people with a variety of autoimmune diseases, researchers found that one genetic variant in the gene that codes for the TYK2 protein protects against a wide range of diseases that cause the immune system to attack the body. The variant changes one amino acid in the protein. As a result, the protein's activity is greatly reduced, but not completely eliminated, researchers report November 2 in Science Translational Medicine.
The researchers say the variant strikes just the right balance between incapacitating the immune system and protecting against overreactions that lead to multiple sclerosis, Crohn's disease and other autoimmune disorders. New drugs that reduce TYK2's activity would need similar Goldilocks-like precision. But if such a drug could be developed, it could prove useful against a broad range of diseases.
Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. In molecular genetics from Washington University in St. Louis and a master's degree in science journalism from Boston University.
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