Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

• Published in: Respiratory research Vol. 23; no. 1; pp. 152 - 12
• Main Authors: Lopez-Campos, José Luis, Osaba, Lourdes, Czischke, Karen, Jardim, José R., Fernandez Acquier, Mariano, Ali, Abraham, Günen, Hakan, Rapun, Noelia, Drobnic, Estrella, Miravitlles, Marc
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.06.2022; BioMed Central; BMC
• Subjects: A1 gene; Alleles; alpha 1-Antitrypsin - genetics; Alpha 1-antitrypsin deficiency; alpha 1-Antitrypsin Deficiency - diagnosis; alpha 1-Antitrypsin Deficiency - epidemiology; alpha 1-Antitrypsin Deficiency - genetics; Alpha1 antitrypsin deficiency; Asthma; Bronchiectasis; Buccal swab; Chronic obstructive pulmonary disease; Complications and side effects; Confidentiality; Cross-Sectional Studies; Diagnosis; Diagnostic systems; Diagnostic tests; DNA sequencing; Dried blood spots; FDA approval; Feasibility Studies; Gene sequencing; Genetic aspects; Genotype; Genotyping; Humans; Laboratories; Lung diseases, Obstructive; Mutation; Patients; Pulmonary Disease, Chronic Obstructive - diagnosis; Registration; Respiratory diseases; Risk factors; Severe acute respiratory syndrome coronavirus 2; Spain; Brazil; Colombia; Argentina; Turkey; Chile; Diagnosis; Genotyping; Alpha1 antitrypsin deficiency; Buccal swab; Dried blood spots
• ISSN: 1465-993X; 1465-9921; 1465-993X
• DOI: 10.1186/s12931-022-02074-x

Currently, strategies for improving alpha1 antitrypsin deficiency (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, Colombia, Spain, and Turkey. 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-specific 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 mutations 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. The study included 30,827 samples: 30,458 (94.7%) with final 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 prevalence 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 identified. 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 presented AATD mutations. Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.