Alpha1-antitrypsin deficiency in Greece: Focus on rare variants.

PURPOSE

AAntitrypsin deficiency (AATD) pathogenic mutations are expanding beyond the PIZ and PIS to a multitude of rare variants.

AIM

to investigate genotype and clinical profile of Greeks with AATD.

METHODS

Symptomatic adult-patients with early-emphysema defined by fixed airway obstruction and computerized-tomography scan and lower than normal serum AAT levels were enrolled from reference centers all over Greece. Samples were analyzed in the AAT Laboratory, University of Marburg-Germany.

RESULTS

Included are 45 adults, 38 homozygous or compound heterozygous for pathogenic variants and 7 heterozygous. Homozygous were 57.9% male, 65.8% ever-smokers, median (IQR) age 49.0(42.5-58.5) years, AAT-levels 0.20(0.08-0.26) g/L, FEV(%predicted) 41.5(28.8-64.5). PIZ, PIQ0, and rare deficient allele's frequency was 51.3%, 32.9%,15.8%, respectively. PIZZ genotype was 36.8%, PIQ0Q0 21.1%, PIMdeficientMdeficient 7.9%, PIZQ0 18.4%, PIQ0Mdeficient 5.3% and PIZrare-deficient 10.5%. Genotyping by Luminex detected: p.(Pro393Leu) associated with M (M1Ala/M1Val); p.(Leu65Pro) with M; p.(Lys241Ter) with Q0; p.(Leu377Phefs24) with Q0 (M1Val) and Q0 (M3); p.(Phe76del) with M (M2), M (M1Val), M (V) and Q0 (S); p.(Asp280Val) with P (M1Val) P (M4) Y (p.Pro39His). Gene-sequencing (46.7%) detected Q0, Q0, Q0 M, N and one novel-variant (c.1A>G) named Q0.Heterozygous included PIMQ0 PIMM PIMp.(Asp280Val), PI*MO AAT-levels were significantly different between genotypes (p = 0.002).

CONCLUSION

Genotyping AATD in Greece, a multiplicity of rare variants and a diversity of rare combinations, including unique ones were observed in two thirds of patients, expanding knowledge regarding European geographical trend in rare variants. Gene sequencing was necessary for genetic diagnosis. In the future the detection of rare genotypes may add to personalize preventive and therapeutic measures.