Molecular diagnosis has become essential in the study of inborn errors of immunity

• Health in Code sponsored the symposium “Primary causes of immune dysregulation disorders: the role of genetic testing in the process of diagnosing autoimmune/autoinflammatory disease” at the 44th Congress of the Spanish Society of Immunology, with the participation of doctors Ivona Aksentijevich and Elena Hsieh.


• José María García-Aznar, Head of Immunology at Health in Code, and Dr. Yvelise Barrios, professor of immunology at the University of La Laguna, moderated the symposium.


Madrid, 16 de mayo de 2023.

Health in Code has reconfirmed its dedication to immune diseases by sponsoring the symposium “Primary causes of immune system dysregulation: The role of genetic study in the diagnostic process of autoimmune and autoinflammatory diseases” at the 44th Congress of the Spanish Society of Immunology. The congress was hosted in Bilbao and brought together immunology professionals from all over the world.


Dr. Ivona Aksentijevich, from the National Human Genome Research Institute, and Elena Hsieh, from Children’s Hospital Colorado, both eminences in the field of immunology, were in charge of leading the symposium, which was moderated by José María García-Aznar, Head of Immunology at Health in Code, and Dr. Yvelise Barrios, professor of immunology at the University of La Laguna. During the session, discussion focused on the role of genetic testing in identifying mutations involved in monogenic autoinflammatory and autoimmune diseases, both germline and somatic.


In contrast to autoimmunity, the concept of autoinflammation was introduced for the first time in 1999 to classify a group of patients with recurrent fever with no infectious or oncological disease or any presence of antigen-specific antibodies. From a genetic perspective, both monogenic and polygenic forms of autoimmune and autoinflammatory diseases have been identified. In the first group, pathogenicity occurs when one gene is involved, while the disease is polygenic (i.e., multiple genes are involved) or multifactorial (combination of both genetic and non-genetic factors, such as infections, food, microbiota, external agents) in most cases. At the symposium, Dr. Aksentijevich discussed the role of germline and somatic mutations in monogenic autoinflammatory diseases. She elaborated on the molecular mechanisms that explain these diseases, both hereditary and non-hereditary. She emphasized that “molecular diagnosis has become essential in the study of inborn errors of immunity. Monogenic systemic autoinflammatory diseases have been found to be caused by pathogenic mutations in more than 50 genes.” 


During her presentation, Dr. Heish spoke about hypomorphic variants in inborn errors of immunity. These defects complicate predicting the behavior of defective genes responsible for a pathology. When variants of unknown significance that may cause a defect with similar characteristics are identified, some experts believe that standard complementary tests should be implemented to confirm these effects. However, as Dr. Heish comments, “I do not think any generalization can be made because the functions of the genes are very different. Analysis of the function of T cells, or B cells, monocytes, etc. is rather complex, since they are often not similar and there is a number of approaches to evaluate them. Yet I believe that a standardized way to assess the consequence of a new genetic defect and what impact it has on mRNA, phenotype on the immune system, etc. is possible.”


The doctor also touched on the topic of genomics and how it is used in the field of immunological diseases. “In my opinion, going forward will focus on information at the transcription level. Genomics can tell us only it is a variant or a mutation and what is likely to happen and what is not. If a variant has not been detected before, it is difficult to determine if it will have consequences on the immune system at the functional level. However, knowing the impact of the variant/mutation at the level of the transcriptome is very important and can teach us more about the effect it will have on the immune system.” Exhaustive research conducted in rare monogenic cases provides invaluable knowledge that helps us understand how prevalent autoimmune diseases function, which is important for us to develop more targeted treatments and test new therapeutic targets.


José María García-Aznar, Head of Immunology at Health in Code and one of the moderators of the symposium, believes that using the different “omics” tests in a coordinated manner will become a reality for us that will give us a more robust criterion to classify the pathogenicity of variants of uncertain clinical significance “VUS” in the context of these diseases. This would mean that the identification of a VUS by a genetic test could be accompanied by expression analysis, which would enable correlating medical, genetic, and metabolic information to obtain precise data and help in decision-making.


There are specialized laboratories that can offer similar complex functional studies which can shed light on the causality of variants of unknown clinical significance, but it is difficult to extend their reach to all hospital centers and apply and interpret them in all cases. The interpretation of this dataset can be used to develop predictive models. In Spain, we have more and more reference centers and laboratories that specialize in the study of diseases of the immune system. This has created a network that makes it easier for healthcare professionals and patients to access these tests.