The use of commercially available genetic tests in immunodeficiency disorders.

As the gene defects that cause many of the currently recognized immunodeficiency disorders are elucidated, genetic testing is becoming clinically available for most of these disorders. The practicing allergist often has to coordinate the initial immunologic workup for patients with suspected primary immunodeficiencies. The purpose of this review is to inform the practicing allergist of the current availability of testing for genetic defects associated with primary immunologic disorders. In many cases, the allergist may want to refer complex immunologic analyses to an academic referral center. Table 1 is an easy reference for most common primary immunodeficiencies. Although commercial genetic testing is available for an expanding number of genes, this testing is rarely indicated in the initial workup for immunodeficiency. The physician must first consider the phenotypic presentation of the patient and focus the laboratory evaluation based on this presentation. General guidelines for initial immunologic evaluations are reviewed by Ballow1 and in Middleton’s Allergy: Principles and Practice.2 Specifically, if evaluating a patient for a suspected phagocytic defect, the physician should obtain repeated evaluation of the absolute neutrophil count and consider further testing for neutrophil chemotaxis, dihydrorhodamine assay, and/or flow cytometry for CD11/18. Possible humoral defects should be evaluated with quantitative serum immunoglobulin levels, specific polysaccharide and protein antibody responses, and the presence or absence of B cells. If a cellular immune defect is suspected, the workup should start with flow cytometric analysis of T-, B-, and NK-cell subsets and in vitro or in vivo evaluation of T-cell function. Identification of a patient with severe combined immunodeficiency warrants immediate referral to a bone marrow transplantation service since acquiring an infection (viral or opportunistic) may compromise the transplantation outcome. Detailed discussions of these initial evaluations may be found in other articles from this miniseries.3–7 In certain cases, such as leukocyte adhesion deficiency type 1, genetic testing is rarely clinically indicated because these diseases can be effectively diagnosed by phenotypic and functional assays and can be managed without the specific gene defect ever having been identified. Genetic testing is not typically required in common variable immunodeficiency (CVID), in this case because known genetic defects cause only a small number of all cases of CVID and would not alter treatment. One exception to this approach, however, is when the B-cell count is low or absent. In this instance, genetic testing for X-linked agammaglobulinemia is warranted since approximately 10% of male patients with CVID have BTK mutations despite the presence of some serum immunoglobulins. Some general points should be considered when ordering gene testing. Genetic testing should only be performed with informed consent from the patient and/or legal guardian. Most genetic laboratories have their own consent forms, often available online. Signed consent forms should always be sent with the laboratory specimen. Gene testing can be run on whole blood samples, and most can also be run on buccal swab samples. Buccal samples are preferred in patients who have undergone bone marrow transplantation, in which whole blood contains donor cells, or in severely leukopenic patients, in which an adequate amount of DNA may be difficult to obtain from blood samples. Pricing has not been included in Table 1. In general, genetic testing for diagnosis of a new mutation through a clinical laboratory is expensive, ranging from several hundred to several thousand dollars per gene. The cost of genetic testing in a relative of a proband with a known mutation costs considerably less, and prenatal testing for a known mutation often costs much more, but these are situations less frequently encountered by the practicing allergist.