Rare Alpha-1 Antitrypsin Variants in Ireland

Title: Rare Alpha-1 Antitrypsin Variants in Ireland
Author(s): T. Carroll O. Cahalane I. Ferrarotti S. Ottaviani G. McElvaney
Institution: RCSI
Poster: Click to view poster
Category: COPD/Asthma
Abstract: AAT deficiency (AATD) is a genetic condition caused by mutations in the SERPINA1 gene. It can cause chronic obstructive pulmonary disease (COPD), liver disease and panniculitis. Over 200 SERPINA1 mutations exist in addition to the well described Z mutation (p.Glu342Lys). AATD continues to be under-diagnosed in Ireland despite its high prevalence.

21,000 individuals have been screened for AATD following ATS/ERS guidelines as part of a HSE-funded national targeted detection programme. AAT quantification is by turbidimetry and AAT phenotyping is by isoelectric focusing. Rare SERPINA1 mutations are identified by DNA sequencing.

We identified a large number of rare AAT mutations including I, F, Null (Q0), Etokyo, Mmalton, Mwurzburg, Plowell, Smunich, Xchristchurch, and Zbristol. The I mutation (p.Arg39Cys) is most common with 182 cases, with 85 cases of the F mutation (p.Arg223Cys). The most common severe mutation is Mmalton (p.Phe52del, 15 cases). In addition, 7 novel mutations were identified, including the novel Null mutations Q0dublin and Q0cork. The rare intronic Null mutation, Q0porto was also identified in 3 cases.

Rare mutations were detected in 1.5% of individuals screened with many causing profound serum AAT deficiency. Our findings highlight the importance of a comprehensive diagnostic approach to AATD that includes phenotyping, genotyping and if necessary, DNA sequencing.