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Background: α1-Antitrypsin (AAT) deficiency variants reduce the concentration of serum AAT protease inhibitor and can lead to the development of pulmonary and hepatic disease. Relative frequencies of rare AAT variant phenotypes (non-M, Z, and S) and associated serum concentrations in the clinical population have not been thoroughly described., Methods: Protein phenotypes were determined by isoelectric focusing electrophoresis for 72,229 consecutive samples. Phenotype frequencies, median serum concentrations, and central 95% concentration intervals were determined for observed phenotypes. Concurrent AAT phenotype and concentration data were used to evaluate the efficacy of using serum AAT concentration alone to detect AAT deficiency., Results: Age, race, and sex had only slight effects on the median 95% serum protein concentration intervals of the 58,087 PiMM (wild type) phenotype specimens. Positive predictive values were calculated for the detection of potential deficiency phenotypes at different serum cutoff concentrations, aiding potential screening effort design. For example, the PiZZ deficiency phenotype (n = 814) could be detected at 99.5% sensitivity and 96.5% specificity using a cutoff of ≤ 85 mg/dL. However, at-risk specimens with two putative deleterious variants (Z, S, I, F, P, T, and Null variants) were detected with only 85.9% sensitivity at this cutoff (n = 1,661). Rare phenotype variants were observed in 2.5% of samples., Conclusions: This analysis provides novel information on serum AAT concentrations associated with different AAT phenotypes and provides insight into the severity of depression of AAT concentration in the presence of rare deficiency variants. Additionally, it allows for evaluation of efficacy of testing algorithms incorporating AAT serum concentration determination.

Background: Alpha-1-antitrypsin (AAT) deficiency is a relatively common genetic disorder that can lead to the development of pulmonary disorders. Diagnosis of AAT deficiency is typically performed by isoelectric focusing (IEF) protein phenotyping in concert with determination of AAT serum concentration levels. The "P" phenotypic variant is associated with several known genetic variants that are found at unknown relative frequencies., Aims: To investigate the genetic variation of "P" alleles in patient samples., Methods: A DNA sequencing protocol for the full AAT coding region from serum was developed. Additionally, a retrospective evaluation of AAT concentrations in serum samples containing "P" allele IEF phenotype variants was undertaken., Results: "P" phenotypic variants are observed in approximately 1 of every 900 samples received in the reference laboratory. Heterozygous "MP" allele samples exhibited a wide range of serum protein concentrations. Genotyping revealed the presence of the deleterious P lowell variant in six heterozygous MP samples, two heterozygous PZ samples, and one homozygous PP sample. A non-deleterious P st albans variant was observed in a single MP sample. A novel heterozygous AAT M"P" variant, P salt lake was identified, that did not exhibit a reduced AAT serum concentration., Conclusions: Genetic heterogeneity is present in clinical "P" phenotype variants identified by IEF, and the deleterious P lowell variant appears to be relatively common. Sequencing of "P" phenotype variants can provide useful clinical information, especially when the "P" phenotype variant is paired with a deficiency phenotype allele.

An integrative diagnostic algorithm for alpha1-antitrypsin (AAT) deficiency testing in the clinical laboratory was developed and evaluated. A novel rapid LightCycler (Roche, Indianapolis, IN) molecular assay was used to detect the common S and Z deficiency allelic variants. However, use of such molecular assays for these variants also can result in the misclassification of significant numbers of "at-risk" patient samples containing other rare AAT deficiency alleles. In the diagnostic algorithm presented herein, patient samples with selected genotypes that exhibit abnormally low AAT concentrations by immunoassay are phenotyped by isoelectric focusing. To test the efficacy of this algorithm, we retrospectively evaluated a data set of 50,020 serum samples for which protein phenotype and AAT concentration had been determined. This algorithm can successfully detect the majority of at-risk samples containing rare deficiency alleles.

The article discusses a study that evaluated alpha 1-antitrypsin phenotypes and associated serum protein concentrations in a large clinical setting. Through isoelectric focusing electrophoresis for 72,229 consecutive samples, protein phenotypes were determined. Age, race, and sex had slight impact on the median 95-percent serum protein concentration intervals of the 58,087 wild type phenotype specimens. It is said that the study allows for evaluation of efficacy of testing algorithms.