Molecular diagnostics of α1-antitrypsin deficiency

Diagnosis of α1-antitrypsin (AAT) deficiency is based on serum protein level, phenotyping and genotyping. Each of these methods has serious limitations and not enough accuracy to be used alone. Combinations of two different techniques are recommended to increase the reliability of AAT deficiency testing. Changes of AAT serum levels can result from clinical conditions and the inflammatory response may increase protein level. Phenotyping discriminates AAT variants due to the altered isoelectric point of the protein. It can detect numerous mutations, but often fails in the presence of rare, unknown or null alleles. Genotyping assays can detect or exclude specific mutations. The results are reliable and definitive, but restricted to the most common variants. DNA techniques for AAT gene screening and detection of new variants are available, but these are of limited value as sequencing is required to confirm the results. This review describes common approaches used in AAT deficiency testing and discusses their strengths and weaknesses. A novel functional test for the rapid discrimination of patients with AAT deficiency would greatly enhance diagnostic algorithms.