Rare alpha-1 antitrypsin mutations in the Irish population

AAT deficiency (AATD) results from mutations in the SERPINA1 gene, classically presenting with early-onset emphysema and liver disease. The most common mutation causing AATD is the Z mutation, with the S mutation weakly associated with lung disease. AAT deficiency is under-diagnosed and prolonged delays in diagnosis are common. ATS/ERS guidelines advocate screening all COPD, poorly-controlled asthma, and cryptogenic liver disease patients, as well as first degree relatives of known AATD patients. 5,000 individuals were screened following ATS/ERS guidelines as part of the Irish national targeted detection programme. AAT levels were determined by nephelometry. AAT phenotyping was performed by isoelectric focussing. Patient DNA isolated from DBS samples was genotyped by PCR (Roche LightCycler). Rare and novel mutations were identified by DNA sequencing of the SERPINA1 gene. A number of rare SERPINA1 mutations including I, V, F, Xchristchurch, Zbristol, and Mmalton were identified. The I mutation (Arg39Cys) was present at a relatively high frequency (0.0038) in a targeted population, with over 40 cases identified. In addition, a new SERPINA1 mutation was identified. Current testing of suspected AATD cases is often limited and can miss rare and novel clinically significant SERPINA1 mutations. The rare mutations described in this study were not detected by a commonly used genotyping assay, however, the low AAT levels prompted their correct identification using more detailed genetic analysis. Our findings underline the need for a comprehensive diagnostic work up of all patients with low AAT levels including phenotyping, genotyping and if necessary, DNA sequencing of the SERPINA1 gene.