Snyder and Fantz present an interesting case of α1-antitrypsin (A1AT) deficiency caused by homozygosity for the Z-deficiency allele. Although A1AT deficiency is generally associated with the Z and/or S alleles, other deficiency alleles also occur. The clinical laboratory is faced with the challenge of detecting all clinically relevant alleles in a timely and cost-effective manner. Phenotyping by isoelectric-focusing electrophoresis has been used for many years to identify a wide range of alleles. Although commercial reagent sets are available, phenotyping remains technically demanding. In addition, commercial standards are available only for the S and Z alleles. Recently, DNA-based genotyping has generated interest as an alternative to phenotyping. Because most genotyping assays focus on detection of only the S and Z alleles, however, at least 2 groups of investigators have developed diagnostic algorithms for A1AT deficiency that include quantification, genotyping, and phenotyping (1)(2). The testing begins with measurement of A1AT concentration and genotyping for the S and Z alleles. An A1AT concentration that is lower than expected for the observed genotype suggests the presence of another deficiency allele, a result that requires reflex testing with a method that enables identification of numerous alleles. If phenotyping is selected, in-house comparison samples must be accumulated to permit accurate identification of rare deficiency alleles. Even theoretically, however, it is impossible to collect all potential phenotypes. Alternatively, DNA sequencing can be used to identify rare, deleterious alleles. Although more expensive, sequencing can detect null alleles, is not subject to inference by replacement therapy, and does not require a sample bank of unusual phenotypes. DNA sequencing may become an important component of diagnostic algorithms for A1AT deficiency (3)(4).
Despite efforts to raise awareness of this relatively common genetic disorder, A1AT deficiency remains underdiagnosed. Detailed recommendations for diagnostic testing for symptomatic individuals and asymptomatic individuals who are at increased risk for carrying deficiency alleles have been established (5). Clearly the clinical laboratory will continue to play a central role in the implementation of these recommendations and thus in the diagnosis of A1AT deficiency.
Grant/Funding Support: None declared.
Financial Disclosures: None declared.
- © 2008 The American Association for Clinical Chemistry