Abstract

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 ∼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.