X-linked severe combined immunodeficiency (SCID) is an inherited disorder of the immune system that occurs almost exclusively in males. Children with X-linked SCID are prone to recurrent and persistent infections because they lack the necessary immune cells to fight off certain bacteria, viruses, and fungi.

If untreated, infants with X-linked SCID can develop poor growth, chronic diarrhea, a fungal infection called thrush, skin rashes, and life-threatening infections. X-linked SCID can be detected shortly after birth by newborn screening, which allows for prompt treatment.

Variants (also known as mutations) in the IL2RG gene cause X-linked SCID. The IL2RG gene provides instructions for making a protein that is critical for normal immune system function. This protein is necessary for the growth and maturation of developing immune system cells called lymphocytes. Lymphocytes defend the body against potentially harmful invaders, make antibodies, and help regulate the entire immune system. Variants in the IL2RG gene prevent these cells from developing and functioning normally. Without functional lymphocytes, the body is unable to fight off infections.

Normal Function

The IL2RG gene provides instructions for making a protein called the common gamma chain. This protein is a component of several different receptors that are involved in immune system function. The receptors span the cell membrane, with one end outside the cell like an antenna and the other end inside to transmit signals to the nucleus. Other proteins attach to these receptors, like a key in a lock, to trigger a series of chemical reactions inside the cell.

Receptors containing the common gamma chain are located on the surface of immature blood-forming cells in bone marrow. They partner with other proteins to direct blood-forming cells to form lymphocytes (a type of white blood cell). The receptors also regulate the growth and maturation of several subtypes of lymphocytes: T cells, B cells, and natural killer cells. These cells kill viruses, make antibodies, and help regulate the entire immune system.

Health Conditions Related to Genetic Changes

X-linked severe combined immunodeficiency

Hundreds of variants (also known as mutations) in the IL2RG gene have been identified in people with X-linked severe combined immunodeficiency (SCID). This condition is an inherited disorder of the immune system that occurs almost exclusively in males. Most of the variants that cause X-linked SCID involve changes in one or a few DNA building blocks (nucleotides) in the IL2RG gene. These changes lead to the production of a nonfunctional version of the common gamma chain or prevent any protein from being produced. Without the common gamma chain, important chemical signals are not relayed to the nucleus and lymphocytes cannot develop normally. A lack of functional mature lymphocytes prevents the immune system from fighting off infections.

Other Names for This Gene

• CD132
• common cytokine receptor gamma chain
• Gamma-C
• IL2RG_HUMAN
• IMD4
• interleukin 2 receptor, gamma
• interleukin 2 receptor, gamma (severe combined immunodeficiency)
• SCIDX
• SCIDX1
• X-SCID
• XSCID
• γc

Genomic Location

X-linked severe combined immunodeficiency (X-SCID) is inherited in an X-linked recessive manner. A condition is X-linked if the changed (mutated) gene responsible for the condition is located on the X chromosome. The X chromosome is one of the two sex chromosomes; females have two X chromosomes, and males have one X and one Y chromosome. In males, one mutated copy of the responsible gene causes signs and symptoms of the condition because they don't have another X chromosome with a working copy of the gene. In females, having one mutated copy of the gene would make them an unaffected carrier; a mutation would have to occur in both copies of the gene to cause the condition. This is why X-linked recessive disorders, including X-linked SCID, occur much more frequently in males. In female infants who have symptoms of SCID, non-X-linked forms of SCID (autosomal recessive forms) should be considered.

The father of a boy with X-SCID cannot have the disease and cannot be a carrier (having a mutated copy of the responsible gene would make him affected). If an affected boy is the only affected family member, either his mother is a carrier or the mutation occurred for the first time in the affected boy (a de novo mutation). It is thought that about 2/3 of these cases are inherited from a carrier mother, and about 1/3 are due to new de novo mutations.

If there is more than one affected family member, it is assumed that the mother of the affected boy is a carrier. A carrier mother has a 50% risk to pass on the mutation in each pregnancy. Males who inherit the mutation will be affected, and females who inherit the mutation will be unaffected carriers. A man with X-SCID will pass the mutation to all of his daughters and none of his sons.

Genetic testing can often determine which family member had the first mutation. Identifying this family member is important for learning which branches of a family are at risk for X-SCID. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing IL2RG mutation has been identified in the family.

People with a family history of X-SCID who are interested in learning about genetic risks to themselves and family members should speak with a genetics professional.

Sources generally refer only to males having X-SCID and we are not aware of reports of any affected females in the medical literature. In order for a female to have X-linked severe combined immunodeficiency (X-SCID), she would have to have a disease-causing mutation in both copies of the disease-causing gene (i.e. on both of her X chromosomes). This is because X-SCID is inherited in an X-linked recessive manner. Theoretically, a female could be affected if:

• she inherits a disease-causing mutation on one X chromosome from a carrier mother, and has a new (de novo) mutation on the gene on the other X chromosome (since it is not possible for her father to be an unaffected carrier)
• she inherits one mutation from a carrier mother, and another from an affected father
• she has two de novo mutations

Again, we are not aware of any reports of affected females. The presence of non-X-linked forms of SCID (autosomal recessive forms) should be considered for female infants who have signs and symptoms of SCID, and for any infant who has physical features of a syndrome associated with the types of immunodeficiencies seen in SCID. Examples may include 22q11.2 deletion syndrome and CHARGE syndrome.

A male cannot be an unaffected carrier of X-linked severe combined immunodeficiency (X-SCID). Because X-SCID is an X-linked recessive condition, a male with a disease-causing mutation in the responsible gene would have the condition. A male could be an unaffected carrier of an autosomal recessive form of SCID.

There is a condition related to X-SCID called 'atypical X-SCID,' in which a mutation in the same disease-causing gene results in production of a small amount of the gene product, or a protein with residual activity (i.e. the mutation is less severe). Males with this type of mutation may have an unregulated immune response and autoimmunity associated with rashes, gastrointestinal malabsorption, an enlarged spleen, and short stature.

Children born with a rare genetic disorder called X-linked severe combined immunodeficiency (X-SCID) don’t have a functioning immune system. As a result, they can’t fight off infections. Without treatment, an infant with X-SCID will usually die within the first year or two of life.

The best option for treatment of newly diagnosed infants with X-SCID has been stem-cell transplantation from a genetically matched sibling. But less than a quarter of children with X-SCID have a matched donor available. For those without a matched donor, standard treatment has been a half-matched bone marrow transplant from a parent. But most infants receiving this type of transplant only have part of their immune system, called T lymphocytes, restored. These infants will need lifelong injections of protective antibodies. In addition, as they grow into young adulthood, they may have chronic medical problems that affect growth, nutrition, and quality of life.

To develop a better approach to fix the immune systems of children with X-SCID, researchers have used gene therapy to alter patients’ own blood stem cells. An engineered virus brings a healthy copy of the gene into the stem cells to replace the mutated gene that causes the disease.

Early results from trials of gene therapy for X-SCID resulted in life-saving correction of T lymphocytes. But similar to bone marrow transplant from a parent, the immune restoration was incomplete. In addition, in those first gene therapy studies, almost a third of the children developed leukemia. The approach accidentally stimulated cells to grow uncontrollably. In later studies, improved design of the engineered virus didn’t cause cancer, but also didn’t fully restore a healthy immune system.

In 2010, Dr. Harry Malech of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Brian Sorrentino of St. Jude Children’s Research Hospital reported a new and safer version of gene therapy for X-SCID. They designed a harmless engineered virus (called a lentivector) that could deliver genes into cells without activating other genes that can cause cancer. Before the altered stem cells were returned to their bodies, patients were given low doses of the chemotherapy drug busulfan. This made it easier for the new stem cells to grow in the bone marrow. In young adults and children treated at the NIH Clinical Center, the new therapy proved to be both safe and effective at restoring the full range of immune functions.

Based on this work, a team led by Dr. Ewelina Mamcarz of St. Jude Children’s Research Hospital began treatment in 2015 of newly diagnosed infants with X-SCID using the lentivector and busulfan. The work was funded in part by NHLBI. The team described the treatment of eight infants with the disorder on April 18, 2019, in the New England Journal of Medicine.

By 3 to 4 months after infusion of the repaired stem cells, 7 of the 8 infants had normal levels of multiple types of immune cells in their blood. The last infant required a second stem-cell infusion, after which his immune-cell levels rose to a normal range.

The infants’ new immune systems were able to fight off infections that the researchers had detected before the gene therapy. Four of the eight discontinued immune-system boosting medications that they’d previously needed. Of those four, three developed antibodies in response to vaccination, indicating a fully functional immune system.

A year and a half after gene therapy, all children were healthy and growing normally.

“The broad scope of immune function that our gene therapy approach has restored to infants with X-SCID — as well as to older children and young adults in our continuing study at NIH — is unprecedented,” Malech says.

The researchers will continue to follow the participants over time. They plan to track how the children’s immune systems develop and look for any late side effects.

X-linked SCID is the most common form of a group of severe combined immunodeficiency disorders. This group of disorders can be caused by variants in more than 20 genes. The incidence of all severe combined immunodeficiency disorders is 1 in 60,000 newborns and it is estimated that one-quarter to one-third of these cases are X-linked SCID.