TYPE: Abstract TOPIC: Genetic and Developmental Disorders PURPOSE: This study aimed to investigate genotype and phenotype characteristics of a Greek cohort of A1AT deficiency patients. METHODS: A1AT deficiency patients followed-up in Greece and analyzed in A1AT Laboratory, Universitätsklinikum Gießen und Marburg GmbH, Germany were enrolled in the study. Patients underwent A1AT measurement for early emphysema RESULTS: Included are 24 adults, 54.2% males, 28.6% never-smokers, diagnosed at a median age (IQR) of 49 (43.0-59.5) years with A1AT levels of 0.255 (0.185-0.380) g/L. Patients presented with a median (IQR) FEV1 (% predicted), FEV1/FVC% and DLCO (% predicted) of 40.9 (29.9, 59.8), 50.5 (39.3, 63.0) and 52.8 (35.8, 68.0) respectively. Ten patients (41.7%) presented PI*ZZ genotype, 4 patients (16.7%) PI*Q0Q0 genotypes and 3 patients (12.5%) PI*ZQ0 genotypes. Q0 alleles corresponded to PI*Q0-Bellingham (1/7pts), PI*Q0-Amersfoort (3/7 pts) and PI*Q0-Granitefalls 3/7pts), ultra-rare null variants. Four patients (16.7%) were carriers of at least one of the following rare variants MHeerlen, MProcida and MMalton. In 3 patients (12.5%) sequencing indicated other ultra-rare mutations. Null variants were significantly associated with lowest A1AT levels and lower FVC values, compared to other variants [p=0.023 and p=0.034 respectively]. A1AT protein levels significantly correlated to FEF25-75% (% predicted) [p=0.013, r=0.559] CONCLUSIONS: The present study provides new evidence about an increased incidence of rare and ultra-rare A1AT variants in Greece of clear pathogenic significance, confirming an established North to South European geographical trend in A1AT deficiency. CLINICAL IMPLICATIONS: The interpretation of novel SERPINA1 variants highlighted the importance of unravelling new mechanisms of A1AT deficiency pathophysiology in a personalized medicine era DISCLOSURE: Nothing to declare. KEYWORD: A1 ANTITRYPSIN DEFIECIENCY