Rare SERPINA1 variants leading to severe Alpha-1 Antitrypsin Deficiency

<bold>INTRODUCTION:</bold> Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by variants in the SERPINA1 gene which can lead to lung, liver, and skin disease. The most common pathological SERPINA1 variant is Z (p. Glu342Lys, rs28929474), present in 1 in 25 Irish people (Carroll et a1, 2011). European Respiratory Society (ERS) guidelines advocate targeted testing for AATD in COPD, poorly-controlled asthma, cryptogenic liver disease and panniculitis patients, as well as first degree relatives. <bold>METHODS:</bold> 24,500 Irish individuals have been screened following ERS guidelines in a national targeted detection programme. Serum AAT quantification is by turbidimetry. AAT phenotyping by isoelectric focusing allied to confirmatory allele-specific genotyping when required. Rare and novel variants are identified by SERPINA1 gene sequencing. <bold>RESULTS:</bold> We have identified a number of rare SERPINA1 variants that cause severe AAT deficiency in a national targeted detection programme for AATD. These include Mmalton, Mwurzburg, Mheerlen, and nonsense or null (Q0) variants that produce no detectable AAT protein in routine quantitative assays. A total of six different Null variants have been detected, Q0amersfoort, Q0bolton, Q0lisbon, and Q0porto, in addition to 2 novel mutations Q0dublin and Q0cork (Ferrarotti et al, 2014). <bold>CONCLUSION:</bold> Our study underlines the importance of multiple approaches to investigating AATD, including phenotyping, allele-specific genotyping, and SERPINA1 sequencing (Franciosi et al, 2019). As testing for AATD increases, it is likely that additional rare SERPINA1 variants causing severe AATD will be discovered.