A Library of Rare α1-Antitrypsin (AAT) Variant Phenotypes to Aid in the Diagnosis of AAT Deficiency

α1-Antitrypsin (AAT) deficiency is a hereditary disorder due to defective production of the serine protease inhibitor, AAT, which can cause lung and liver diseases. Severity of disease depends particularly on the phenotypic representation of AAT variants in the patient.

In this study, we present determination of seven common and nine rare variant phenotypes of AAT using pediatric samples collected in Texas Children's Hospital to address the knowledge gap in the identification of rare variants. We tested 16 different AAT variants that had been stored in a -80 °C freezer over the years to add to the reference library of AAT variants. The gold-standard isoelectric focusing electrophoresis method was used for analysis and interpretation of AAT variants. Each variant was inspected visually by comparing multiple bands, unique to phenotypic identity, with a previously identified pattern.

Seven common M, S, and Z variants were identified as M1M1, M2M2, M1M2, MS, SS, SZ, and ZZ. Nine rare variants were identified as FM, FS, FZ, PM, XM, YM, IM, TS, and EP. These were interpreted independently and in a blinded manner by an experienced technologist and two clinical chemists from two different institutions.

Our results add to the reference library to identify the rare variant phenotypes of AAT protein. This report will guide clinical laboratories for proper assessment of rare variants and in turn contribute to accurate diagnosis and management of AAT deficiency.