MOLECULAR AND GENETIC ASPECTS OF X-LINKED SEVERE COMBINED IMMUNODEFICIENCY(SCIDX1) 4

The X-linked form of severe combined immunodeficiency (SCID) accounts for approximately 30-40% of all cases of SCID. The clinical phenotype is indistinguishable from other varieties of SCID, presenting in the first few months of life, with severe infection, failure to thrive, and diarrhoea. There is no previous family history in approximately 30% of cases, the new mutation rate being high for X-linked disorders. The typical immunological phenotype includes absence of T cells, but normal or high circulating B cells, usually with absent immunoglobulin production.

The gene responsible for SCIDX1 is located in Xq13, and codes for the`common γ chain' (γ<sub>c</sub>), which is a component of multiple cytokine receptors, including IL2, IL4, IL7, IL9 and IL13. The multiple roles of γ<sub>c</sub> are consistent with the severe clinical phenotype of its deficiency state. Female carriers of SCIDX1 show a unilateral pattern of X chromosome inactivation in purified T cells, implying that γ<sub>c</sub> is essential for normal T cell development. The precise role of γ<sub>c</sub> in T cell development and function is not known. Its interaction with components of the T cell activation pathway will be discussed In `sporadic' cases of T-/B+ SCID the suspicion of γ_c deficiency can be confirmed by demonstration of lack of γ_c expression on mononuclear cells. Demonstration of unilateral X-inactivation in maternal T cells also provides supportive evidence. Identification of a disease-causingγ_c mutation confirms the diagnosis.

A large number of mutations have been identified in the γ_c gene, affecting all eight exons. There is no reliable genotype/phenotype correlation, although one family with a mild phenotype and a mutation causing a conservative amino acid substitution has been described. Two cases of SCIDX1- confirmed by demonstration of a disease-causing mutation in theγ_cgene - have been described who have absent B cells, in contrast to boys with the `typical' B+ phenotype.

Using single strand conformational polymorphism (SSCP) analysis as a screen, mutations can be identified in approximately 85% of cases. Sequencing of the whole gene identifies a few more, but some cases remain where no mutation is found. These boys may have mutations in non-coding control sequences, and some do not have SCIDX1. Some will be found to have Jak3 kinase deficiency - which causes an autosomal recessive form of B+ SCID.

Accurate carrier detection and prenatal diagnosis is possible when disease-causing mutation is known. If no mutation can be found, families with a clear X-linked pedigree can be offered carrier assessment and prenatal diagnosis using T cell X-inactivation analysis and genetic linkage studies.