Genetic Diagnosis of Alpha-1 Antitrypsin Deficiency; core laboratory experience

<bold>Introduction:</bold> Alpha 1 antitrypsin deficiency (AATD) is an autosomal recessive condition, significantly underdiagnosed, in which the presence of a deficient protein or absence of protein can lead to lung and/or liver disease. More frequent variants found in patients with severe AATD are Z and S, but more than 500 genetic variants are identified in SERPINA1 gene (coding gene for AAT). Strategies to improve diagnosis of AATD include genetic testing not limited to Z and S variants identification, and full gene sequencing analysis. Grifols-Progenika diagnosis system offers a quick, simple, and reliable genetic method for sample analysis: 14 genetic variants are tested by A1AT Genotyping Test and followed, when needed, by full gene sequencing <bold>Methods:</bold> Genetic analysis of Dried Blood Spots (DBS) or buccal swab samples was performed at central laboratory in Spain. Allele-specific genotyping was carried out using the Progenika A1AT Genotyping Test, that identifies the 14 most frequent deficiency variants of the SERPINA1 gene. Genotyping was completed by full SERPINA1 gene sequencing when none of the 14 mutations were found or when one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl <bold>Results:</bold> More than 70000 samples were analyzed from 6 countries between March 2018 and December 2023. Beside the frequent variants, Z and S, rare alleles were found in samples from all countries on a relative high frequency. Moreover, variants not previously reported were identified by full gene sequencing <bold>Conclusion:</bold> Genetic analysis including less frequent variants identification and full gene sequencing for discovering new deficient variants can help to improve the diagnosis of AATD