The final results of European external quality control program for laboratory testing of alpha1-antitrypsin deficiency (AATD EARCO LABNet) 2019-2022

Alpha1-antitrypsin deficiency (AATD), despite being one of the most common rare metabolic disorders, is frequently under/misdiagnosed. Accurate laboratory testing using validated methods is crucial for establishing clinical diagnosis, adjusting therapeutic decisions and preventive measures. To ensure high quality of biochemical and genetic testing for AATD we have established the European external quality assessment (EQA), which has been implemented in 7 leading European laboratories during 2019-2022. EQA consisted of 6 rounds. Coordinating centers provided 5-6 blinded reference materials of serum and dried blood spots (DBS) comprising normal and AAT deficient samples. Samples were processed and analyzed according to the site’s routine diagnostic protocols, including AAT concentration, phenotype and/or genotype assessment. Reported results were verified by the referral lab. The reported AAT concentrations in serum and DBS demonstrated mean deviation rates of 9.6-15.4% and 7.9-43.0%, respectively, across rounds. Results of pheno/genotyping assays in samples with common <italic>SERPINA1</italic> deficient variants (Z,S) all had an almost perfect interrater agreement (k>0.81) among labs. There were significant discrepancies for rare variants detection (k=0,7622 and 0,7703 for pheno/genotyping, respectively). The EQA results showed an exemplary interlaboratory concordance in common deficiency variants detection and highlighted the issue of identification and reporting of rare <italic>SERPINA1</italic> variants. Differences observed in DBS-based AAT concentration evaluation may indicate the need to refine the methodology. Unrestrictive grant support by CSL Behring and Grifols.