Mutations are not evenly distributed throughout the gene. 9 Types of (unique) mutations in IL2RG vary and include 55 missense mutations, 33 nonsense mutations, 10 insertions, 32 deletions, and 33 splice mutations types also include complex, large deletions, and mutations that affect RNA processing and translation. Of these mutations, 169 have been documented in only one patient. 1 There are 264 mutations in IL2RG that are known to cause SCID. The IL2RG gene comprises eight exons spanning 5447 base pairs. Another patient had one allele with a large deletion in CD45 and a point mutation that disrupted a splice site in the other allele. 5– 8 One patient was homozygous for a six base-pair deletion that removed a tyrosine residue that is essential to protein function. Mutations in CD45 were identified in three patients with SCID. 3, 4 The majority of these mutations are located in exon 4. A number of mutation sites have been identified, including three nucleotide substitutions that resulted in missense mutations, one nonsense mutation, and one substitution that subsequently resulted in a splice-site mutation. Few patients with IL7R mutations have been studied. 1, 2 Defects in IL7R have been recently implicated in SCID. The IL7R gene comprises eight exons spanning 20,738 base pairs. We conducted an additional search to identify publications describing registries that collected data about patients from populations in a defined geographic area because these articles did not appear in a population-based epidemiology search. We then read the articles’ abstracts to determine which articles were relevant for this particular review. A title search verified that the information in these articles was relevant. These algorithms included all genes and gene-related phrases as well as epidemiologic terms. We also used several search algorithms to locate genetic and epidemiological data from 1990 to 2003. We subsequently did a comprehensive PubMed search (all years covered in the database) for articles about each of the eight genes. These papers were reviewed and presented at a CDC-sponsored conference, “Applying Genetic and Public Health Strategies to Primary Immunodeficiency Diseases,” which took place November 8–9, 2001 (see ). We searched PubMed for all articles published from 1997 to 2001 that included the following key words: “severe combined immune deficiency,” “adenosine deaminase deficiency,” and “combined B- and T-cell immunodeficiencies.” We obtained additional articles by personally locating information in libraries. We used several methods to identify articles relevant to SCID. Validated tests and pilot population studies are necessary to determine newborn screening’s potential for identifying infants with SCID. Because SCID may be unrecognized, with infant deaths from infection attributed to other causes, newborn screening is the only way to ascertain true birth prevalence. Tests for TCLP on dried blood spots could be developed as a screen for SCID. Dried blood spots are currently collected from all infants at birth for newborn metabolic screening. The availability of effective therapies, plus the short asymptomatic period after birth, (when stem-cell transplantation is most effective), make SCID a potentially good candidate for newborn screening. In clinical trials, gene therapy has been used to reconstitute immune function in patients with IL2RG and ADA defects. Currently, hematopoietic stem cell transplants are the standard treatment. Some minimal estimates of SCID prevalence are presented. Population-based genotype and allelic frequencies of these gene defects have not been measured. Mutations in unidentified genes may also cause SCID. Mutations in any of eight known genes: IL2RG, ARTEMIS, RAG1, RAG2, ADA, CD45, JAK3, and IL7R cause SCID. Affected children develop severe bacterial and viral infections within the first 6 months of life and die before 1 year of age without treatment. Severe combined immunodeficiency (SCID) is an inherited immune disorder characterized by T-cell lymphopenia (TCLP), a profound lack of cellular (T-cell) and humoral (B-cell) immunity and, in some cases, decreased NK-cell number and function.
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