Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

Abstract

Background Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. Methods This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. Results There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. Conclusions The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.

Alpha-1 Antitrypsin PI M Heterozygotes with Rare Variants: Do They Need a Clinical and Functional Follow-Up?

“…We suppose that their number will increase further, as the most recent AATD position statement of the Thoracic Society of Australia and New Zealand has expanded the indication of AATD tests in all patients with chronic airflow obstruction, in asthma patients with persistent airflow limitation, in subjects with emphysema disproportionate to their smoking history or in the presence of liver or skin disease [24]. In addition, the availability of a genotyping test that can be performed not only on dried blood spot samples but also on buccal swabs may implement both the diagnosis of AATD and the identification of new rare PI* allelic variants [25,26].…”

Genetic Epidemiology of Alpha-1 Antitrypsin Deficiency in Macaronesia

“…To select those relating to the prevalence of AATD in the general population, the following criteria were applied: (1) samples made up of healthy unrelated people; (2) minimum sample size of 200 subjects (400 alleles); (3) phenotypes or genotypes characterized with reliable techniques, including isoelectrofocusing, real-time allele-specific PCR, PCR-Luminex [23,24], and gene sequencing. With this methodology, three studies carried out in the general population of Madeira [7], La Palma (Canary Islands) [11], and Cape Verde [22] were selected.…”