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Observational Study
. 2022 Jun 10;23(1):152.
doi: 10.1186/s12931-022-02074-x.

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

José Luis Lopez-Campos  1   2 , Lourdes Osaba  3 , Karen Czischke  4 , José R Jardim  5 , Mariano Fernandez Acquier  6 , Abraham Ali  7 , Hakan Günen  8 , Noelia Rapun  3 , Estrella Drobnic  9 , Marc Miravitlles  10   11
Affiliations
Observational Study

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

José Luis Lopez-Campos et al. Respir Res. .

Abstract

Introduction: 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.

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-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.

Results: 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.

Conclusions: 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.

Keywords: Alpha1 antitrypsin deficiency; Buccal swab; Diagnosis; Dried blood spots; Genotyping.

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Conflict of interest statement

JLLC has received honoraria during the last three years for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetical order): AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Laboratorios Esteve, Laboratorios Ferrer, Gebro Pharma, GlaxoSmithKline, Grifols, Menarini, Novartis, Rovi, and Teva. MM has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Inhibrx, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, pH Pharma, Palobiofarma SL, Takeda, Novartis, Sanofi and Grifols and research grants from Grifols. AA has received speaker fees from Astra Zeneca, Boehringer Ingelheim, Chiesi (Amarey), Cipla, Zambon, and Novartis, consulting fees from Sanofi, GlaxoSmithKline, Glenmark and research grants from Grifols, Boehringer Ingelheim and Astra Zeneca. HG has received honoraria for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetical order): Abdiİbrahim, AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Dem Pharma, Deva, Eczacıbaşı, Exeltis, GlaxoSmithCline, Grifols, ILKO, NeuTec, Nobel, Novartis, Pfizer, Pharmactive, Recordati, Roche, Sandoz and VEM. MFA has received honoraria during the last five years for lecturing, scientific advice, participation in clinical studies or writing for publications for: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Novartis and Tuteur.

Figures

Fig. 1
Fig. 1
Flow chart of the current distribution of the cases in the different steps of the procedure. Results expressed in absolute numbers in total and by geographical area. The Progenika system is a live circuit currently in use, so there are samples in all steps of the procedure
Fig. 2
Fig. 2
Number of cases detected by familiar screening in each different location. Red: cases detected by familiar screening. Grey: index cases
Fig. 3
Fig. 3
World map showing the ratio testing/population, the hit rate and the percentage of Z and S alleles. This is not an accurately scaled map
Fig. 4
Fig. 4
Allele distribution according to the different genotyping reasons
See this image and copyright information in PMC

References

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