Alpha1-antitrypsin deficiency in Greece: Focus on rare variants

A₁Antitrypsin deficiency (AATD) pathogenic mutations are expanding beyond the PI*Z and PI*S to a multitude of rare variants.

to investigate genotype and clinical profile of Greeks with AATD.

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.

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, FEV₁(%predicted) 41.5(28.8-64.5). PI*Z, PI*Q0, and rare deficient allele's frequency was 51.3%, 32.9%,15.8%, respectively. PI*ZZ genotype was 36.8%, PI*Q0Q0 21.1%, PI*MdeficientMdeficient 7.9%, PI*ZQ0 18.4%, PI*Q0Mdeficient 5.3% and PI*Zrare-deficient 10.5%. Genotyping by Luminex detected: p.(Pro393Leu) associated with M_Heerlen (M1Ala/M1Val); p.(Leu65Pro) with M_Procida; p.(Lys241Ter) with Q0_Bellingham; p.(Leu377Phefs*24) with Q0_Mattawa (M1Val) and Q0_Ourem (M3); p.(Phe76del) with M_Malton (M2), M_Palermo (M1Val), M_Nichinan (V) and Q0_LaPalma (S); p.(Asp280Val) with P_Lowell (M1Val)_; P_Duarte (M4)_, Y_Barcelona (p.Pro39His). Gene-sequencing (46.7%) detected Q0_GraniteFalls, Q0_{Saint-Etienne}, Q0_{Amersfoort(M1Ala),} M_Würzburg, N_Hartfordcity and one novel-variant (c.1A>G) named Q0_Attikon.Heterozygous included PI*MQ0_{Amersfoort(M1Ala),} PI*MM_Procida, PI*Mp.(Asp280Val), PI*MO_Feyzin. AAT-levels were significantly different between genotypes (p = 0.002).

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.