Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin defciency: a multinational cross‑sectional analysis

Abstract

Introduction: Currently, strategies for improving alpha1 antitrypsin defciency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colom‑ bia, Spain, and Turkey. Methods: This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specifc genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the muta‑ tions were found or one variant was detected in heterozygous status and the AAT serum level was<60 mg/dl, or if requested by the clinician in charge. Results: The study included 30,827 samples: 30,458 (94.7%) with fnal results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The preva‑ lence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identifed. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also pre‑ sented AATD mutations. Conclusions: Our results confrm the viability of this diagnostic system for genotyping AATD conducted simultane‑ ously in diferent countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.