X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency (X-SCID) is inherited in an X-linked recessive manner.^[1] 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.^[1]

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.^[1]

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.^[1] 

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.^[1]

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.

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.^[1]

You can learn more about the different types of SCID and their inheritance patterns on the Immune Deficiency Foundation's Web site.

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.^[1]

The risk to have a child with severe combined immunodeficiency (SCID) would depend on the type of SCID of which each parent is a carrier.

If both parents are carriers of the same autosomal recessive form of SCID, each child would have a 25% (1 in 4) risk to be affected, a 50% (1 in 2) risk to be an unaffected carrier like each parent, and a 25% risk to be affected. These risks apply to both male and female offspring.

If the mother is a carrier of X-linked SCID and the father is a carrier of an autosomal recessive form of SCID, there is only a risk of X-linked SCID in their male children. The mother has a 50% risk to pass on the disease-causing mutation in each pregnancy. All males who inherit the mutation will be affected, and all females who inherit the mutation will be carriers.

Because it is not possible for a male to be an unaffected carrier of X-linked SCID, parents cannot both be carriers of this type.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.