“Alpha1-antitrypsin M-like variants: the importance to detect the Mwhitstable intronic mutation”

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Background: M-like variants are a heterogeneous group of rare AAT mutations displaying the same electrophoretic pattern as the M wild-type protein. For this reason, they are difficult to diagnose with the routine lab methods. We focused on Mwhitstable (g.11640del26bp, insGG) allele, an intronic M-like variant that is poorly studied. Objectives: To better understand the epidemiological impact and the clinical significance of this variant, we analysed the data collected from patients carrying this mutation. Methods: During the routine diagnosis of AATD at our Centre, from January 2017 to December 2024 we identified the Mwhitstable allele by allele specific testing. Results: Mwhitstable variant was detected in 313 out of 15311 subjects (2%), with suspected AATD. The genotypes were: 295 PI*M/Mwhitstable, 12 PI*Z/Mwhitstable, 1 PI*Mmalton/Mwhitstable, 1 PI*S/Mwhitstable and 4 PI*Mwhitstable/Mwhitstable. We deeply characterized 50 patients from this cohort (2 severe and 48 intermediate AATD). Among them, 34 were former or current smokers mean (30 P/Y) and 49 (97%) had one or more major respiratory diseases (asthma, severe asthma, COPD, bronchiectasis, emphysema). Mean AAT plasma level was 124,18 mg/dl (SD 38). As for respiratory function tests: 20 pts had a FEV1/FVC <70% (mean 69% (±22%)) with a mean DLCO of 77% of predicted (±22%). Although there is no known polymerogenic aptitude in Mwhitstable allele, 6 out of 50 patients had hepatic disease (5 steatosis and 1 cyrrosis). Conclusions: Since subjects carrying the Mwhitstable allele seem to have a higher risk of developing lung diseases, an early and accurate diagnosis is needed to improve the clinical management of these patients.

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