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

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.

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

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.

Results of a Diagnostic Procedure Based on Multiplex Technology on Dried Blood Spots and Buccal Swabs for Subjects With Suspected Alpha1 Antitrypsin Deficiency.

INTRODUCTION: The objective of this analysis was the evaluation of a new national circuit used for diagnosing alpha1 antitrypsin deficiency (AATD) based on multiplex technology using online registration and mail posted samples from dried blood spots (DBS) and buccal swabs. METHODS: This is an observational, ongoing study conducted in Spain since March 2018. Samples are coded on a web platform and sent by postal mail to the central laboratory. Allele-specific genotyping for the 14 most common mutations was done with the Luminex 200 Instrument System. Gene sequencing was done if none of the mutations were found and the AAT serum level was <60mg/dl, or by request from the clinician in charge. RESULTS: At the time of the present report, 5803 (92.9%) samples were processed, 4984 (85.9%) from buccal swab and 819 (14.1%) from DBS. The prevalence of the frequent allele combinations were: MS 19.0%, MZ 14.4%, SS 2.9%, SZ 3.7%, and ZZ: 1.4%. Globally, Z carriers represented 20.0% and S carriers 26.6% of this population, with differences seen between regions. 209 (3.6%) were identified carrying rare alleles, 12 (0.2%) carrying null alleles and 14 (0.3%) new mutations were described. Respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. CONCLUSIONS: The availability of a diagnostic system based on the simultaneous testing of 14 genetic variants from buccal swabs or DBS sent by postal mail and with web registration has proven to be useful, and the system can improve the timely diagnosis of AATD.

[Life-threatening hemoptysis: study of 154 patients]. / Hemoptisis amenazante: estudio de 154 pacientes.

BACKGROUND AND OBJECTIVES: The natural history of life-threatening hemoptysis (LTH), a medical emergency, is ill defined. The objective of the study was to evaluate, in a university teaching hospital setting, the etiology, methods used, and evolution of LTH. PATIENTS AND METHODS: Prospective study in which we enrolled 154 patients admitted for LTH over 3 consecutive years. Bronchoscopy and arteriography procedures were performed, as prescribed by the attending physician. Patient evolution was followed 5 years post-event. RESULT: 79.2% were male. Average age was 57 (SD 15) years. Bronchiectasis and active tuberculosis and its consequences were the predominant etiologies. A total of 4.5% patients died as a result of LTH. Bronchoscopy was more effective in identifying the bleeding than arteriography when the examination was performed during an episode of hemoptysis (84.2 versus 20.4%) (P<.001). When embolization or bronchoscopy were used as first measure, embolization was more effective in stabilizing bleeding than bronchoscopy (87 versus 53.5%) (P<.001) in admitted patients. LTH relapse was 10.7%, while it was lower with embolization. CONCLUSIONS: Leading causes were bronchiectasis and tuberculosis. While bronchoscopy during a hemoptysis episode was effective in identifying the source of the bleeding, artery embolization was more effective in stabilizing the patient both at the short and long term.