The immune system and genetics

Genes present on one of the 22 pairs of numbered chromosomes are known as autosomal. In autosomal recessive inheritance, two copies of the PI-causing gene variant must be inherited to cause symptoms of the condition, typically one from each parent.

Usually, each parent of the child affected by an autosomal recessive condition carries one copy of the PI-causing gene variant, and they are unaffected because their other copy of the gene is functional. In this scenario, where both parents are carriers of an autosomal recessive gene variant, there is a 25% chance (1 in 4) that any child, regardless of gender, will be affected by the disorder. There is a 50% chance (1 in 2) that any child will be a carrier (inherit one copy of the variant), and a 25% (1 in 4) that the child will not inherit the at all, and therefore will not be affected by the condition or be able to pass it on to their children.

The chances of a child being affected, a carrier, or neither remain the same for all future pregnancies. The outcome of each pregnancy is independent and is not affected by previous pregnancies.

Examples of autosomal recessive PIs:

• Some forms of severe combined immunodeficiency (SCID).
  • Adenosine deaminase (ADA) deficiency.
  • Recombinase activating gene (RAG) deficiency.
  • JAK3 deficiency.
  • Artemis SCID.
• MHC class II deficiency.
• Three forms of chronic granulomatous disease (CGD).
• Leukocyte adhesion deficiency (LAD).
• Chediak-Higashi syndrome.
• Familial forms of hemophagocytic lymphohistiocytosis (HLH).

Autosomal recessive PIs are rare. Most affected infants do not have any previous family history. However, marriages between people who are related by blood or increased frequency of specific variants in certain populations (such as the Artemis SCID variant in Navajo populations) increase the incidence of such conditions.

Autosomal dominant inheritance is a mode of inheritance where only one copy of the PI-causing gene variant is needed for the disease to occur, regardless of the version of the gene inherited from the other parent. Both males and females can be affected, and there is a 50% chance (1 in 2) of the child of an affected parent inheriting the disease. The risk is the same in every pregnancy.

Sometimes, a patient affected with an autosomal dominant condition will be the first affected person in their family. In this case, the variant spontaneously occurs in the fertilized egg after the joining of egg and sperm.

Examples of autosomal dominant PIs:

• Hyper IgE syndrome, due to STAT3 loss of function (Jobs syndrome).
• Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome.
• Some rare forms of defects in the IFN-γ/IL-12 pathway.
• STAT1 and STAT3 gain of function disorders of immune regulation.

X-linked recessive is a mode of inheritance where the gene variant causing PI is present on the X chromosome. Because males have only one X chromosome, if that X chromosome carries the gene variant, the individual will be affected by the PI. Males have no additional X chromosome to compensate and the Y chromosome does not carry the same set of genes as the X chromosome.

Females have two X chromosomes and must inherit two copies of the gene variant—one from each parent—to develop the disorder. Females are carriers if they inherit one variant because the second copy of the X-linked gene continues to carry out its function. Carriers can pass on the gene variant to their children.

An affected male will pass on the gene variant to 100% of his female children because they will all inherit his X chromosome. In most cases, his daughters will be carriers, unless their mother also happens to be a carrier—then, there is a 50% chance of each daughter being affected.

All of an affected male’s sons will carry the Y chromosome and will therefore neither be affected nor be carriers.

At times, female carriers of X-linked disorders do present with symptoms similar to affected males due to a process called X-inactivation. In this process, which happens during fetal development, some cells shut down (inactivate) the X chromosome inherited from the mother, and other cells inactivate the X chromosome inherited from the father. Which X chromosome each cell inactivates is random.

In the case of an X-linked carrier, if the inactivation happened to the X chromosome coming from the mother, then the only active chromosome will be the X chromosome coming from the father, which carries the disease-causing variant, leading to symptoms similar to the affected males.

Mothers who are carriers can pass on the disease to their sons if the sons inherit the affected X. In this type of inheritance, a family history may show multiple males affected by the disease. Mothers who are carriers can also pass on the affected X to their daughters, who then become carriers of the disease themselves.

Variants in X chromosome genes may also occur spontaneously and may occur in individuals with no previous family history.

Examples of X-linked recessive PIs:

• Bruton’s or X-linked agammaglobulinemia (XLA).
• Wiskott-Aldrich syndrome.
• SCID caused by common gamma chain variants.
• Hyper IgM syndrome, due to CD40 ligand variants.
• Two forms of X-linked lymphoproliferative disease.
• The most common form of chronic granulomatous disease (CGD).
• Properdin deficiency.
• Dyskeratosis congenita.

The chances of a woman who carries a PI-causing X-linked gene variant having an affected child are different based on the gender of the child. If the father is not affected, there are four possible combinations in every pregnancy.

• 25% chance (1 in 4) that a son will inherit the Y chromosome from his father and X-linked recessive gene variant from his mother. He will, therefore, be affected.
• 25% chance (1 in 4) that a son will inherit the Y chromosome from his father and the working copy of the X-linked gene from his mother. He will not be affected by the condition.
• 25% chance (1 in 4) that a daughter will inherit both working copies of the X-linked genes: one copy from her father and one from her mother. In this case, she will not only be unaffected by the condition, but she will also not be a carrier of the X-linked recessive gene variant.
• 25% chance (1 in 4) that a daughter will inherit from her father the working copy of the X-linked gene and the faulty X-linked recessive gene variant from her mother. She will be a carrier of the condition like her mother and will usually be unaffected.

The outcome of future pregnancies is not affected by previous pregnancies, meaning that it is possible for all (100%) of the boys in a family where the mother is a carrier to be affected by the X-linked condition.