Alpha-1 Antitrypsin Gene Variants in Southeastern Türkiye with Identification of Rare Malton Genotypes in a Multicenter Real-world Cohort.

Abstract

Objective: Alpha-1 antitrypsin (A1AT) deficiency is a hereditary disorder associated with an increased risk of chronic obstructive pulmonary disease (COPD) and remains underdiagnosed worldwide. Data from Southeastern Türkiye are limited, particularly in geographically and demographically underrepresented regions of the country. This study aimed to investigate the frequency and spectrum of A1AT gene variants in a real-world multicenter cohort from Southeastern Türkiye.

Material and methods: This retrospective multicenter study included 1,008 patients who underwent targeted genetic testing for A1AT deficiency between 2022 and 2026 at two tertiary centers. Demographic characteristics, smoking status, pulmonary function parameters, and clinical diagnoses were evaluated. A1AT genotypes were classified as normal or variant, the latter including both common and rare alleles.

Results: A1AT variants were identified in 6 patients (0.6%), including the MZ, Lowell, and Malton alleles; one patient carried the rare homozygous Malton/Malton genotype. All variant carriers had COPD. Half of the variant-positive patients were never-smokers, and several demonstrated severe airflow limitation corresponding to Global Initiative for Chronic Obstructive Lung Disease stages 3-4 disease. The overall prevalence of A1AT variants was low and consistent with frequencies previously reported in Mediterranean and Middle Eastern populations. However, the detection of rare alleles highlighted the genetic heterogeneity of A1AT deficiency and suggested that sole reliance on common allele screening may contribute to underrecognition.

Conclusion: Although the prevalence of A1AT variants was low, their detection among high-risk individuals, including never-smokers and patients with severe COPD, underscores the clinical importance of targeted genetic testing. The identification of rare genotypes such as Malton/Malton supports the need for comprehensive genetic evaluation strategies. This study provides important regional data from Southeastern Türkiye and emphasizes the need for larger multicenter studies to better define the epidemiology and clinical impact of A1AT variants.