Genetics and primary immunodeficiencies

The immune system is a versatile defense system involving a variety of cells and mechanisms. From physical barriers such as the skin to phagocytic cells such as macrophages, each component plays a crucial role in protecting against infection. However, when any of these mechanisms fail, as in the case of primary immunodeficiencies, the body is exposed to an increased risk of infectious diseases.

What are primary immunodeficiencies?

Primary immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders that compromise the immune system, predisposing patients to recurrent and severe infections. Our immune system is divided into two groups. The first line of defense, innate immunity, involves physical, chemical and cellular barriers (such as macrophages and neutrophils), offering a rapid but non-specific response to pathogens. Adaptive immunity, on the other hand, is more specific and is based on the action of B lymphocytes, which produce antibodies (humoral immunity), and T lymphocytes, which directly attack infected cells (cell-mediated immunity).

How are they inherited?

Most PIDs are monogenic in origin and can follow an X-linked (XL), autosomal recessive (AR) or autosomal dominant (AD) pattern of inheritance.

What genes are involved?

The range of genes associated with PIDs is wide and continues to be investigated. From genes encoding for T-cell and B-cell receptors to those regulating immunoglobulin production or immune cell maturation, mutations can affect any level of the immune system.

A distinctive feature of PIDs is their great genetic heterogeneity. This means that the same clinical manifestation can be caused by mutations in different genes. For example, agammaglobulinemia can be caused by mutations in the BTK, IGLL1, TCF3 or CD19 gene, among others.

Effects of mutations

Mutations in a gene can cause the function of the protein for which they code to be completely lost, partially decreased or increased.

Loss of Function

The protein encoded by the mutated gene is not produced, is produced in smaller amounts or does not function properly. This loss can be partial or complete, depending on the severity of the alteration. These types of mutations can occur in pathologies of RA or AD inheritance. In the case of RA, there is usually a complete or almost complete loss of protein activity, while in AD there is usually some residual protein activity. Examples of PIDs caused by loss of function include:

• Hyper-IgE syndrome: Hyper IgE syndrome is a genetic disease that causes high levels of IgE in the blood and health problems such as recurrent infections, skin, bone and blood vessel problems. There are two main types: autosomal dominant and autosomal recessive. This syndrome can be caused by mutations that result in a loss of function in the protein encoded by the STAT3 or DOCK8 genes.
• Agammaglobulinemia and hypogammaglobulinemia: These are characterized by low or absent immunoglobulin concentrations and absence of B lymphocytes causing recurrent infections, especially in the upper and lower respiratory tract, gastrointestinal tract, skin and joints. For example, loss of function in GATA2 has an autosomal dominant mode of inheritance and usually debuts in late adolescence or early adulthood.

Gain of Function

Gain of function of a protein occurs when a mutation causes it to increase its normal activity or causes it to acquire new functions that it does not normally possess. For example:

• X-linked congenital severe neutropenia: immunodeficiency syndrome characterized by recurrent severe bacterial infections, neutropenia and monocytopenia. Its mode of inheritance is X-linked and is caused by mutations in the WAS gene that generate an increase in the activity of the protein.

Also, different variants in the same gene can give rise to different phenotypes, for example, in the case of the STAT3 gene some variants can generate a loss of function resulting in Hyper IgE syndrome, while other variants produce a gain of function resulting in systemic autoimmune disease. Another example is the WAS gene, which, depending on the variant present, can result in severe congenital neutropenia, thrombocytopenia or Wiskott-Aldrich syndrome.

Genetic diagnosis

Traditionally, the diagnosis of primary immunodeficiencies is based on a set of functional tests that evaluate the patient’s immune response. These tests include blood cell counts, quantification of immunoglobulin levels, among others. However, this process has its limitations, as it can often become complex and in some cases the results can be non-specific or inconclusive.

Genetic diagnosis has made it possible to identify the specific genetic mutations that cause some of the PIDs. Knowing the underlying genetic cause allows us to confirm the diagnosis more quickly and accurately, which in turn facilitates the implementation of personalized treatments. In addition, genetic diagnosis allows us to offer counseling to families about the risk of transmitting the disease to future generations or to detect other relatives at risk.

Veritas is committed to providing accurate diagnostic options and facilitating their access to as many patients as possible. Veritas in collaboration with the Jeffrey Modell Foundation is leading a project for the early diagnosis of children with primary immunodeficiencies. In addition, Veritas offers to any specialist the primary immunodeficiency panel, a panel that includes the exhaustive analysis of genes associated with these pathologies.