Two Rare Pathogenic AAT Variants Described in New Study

Two rare pathogenic M-like alpha-1 antitrypsin (AAT) variants that increase the risk of developing lung and liver diseases have been described in detail in a new study published in the International Journal of Molecular Sciences.

“The accurate diagnosis of these variants can help the diagnostic process and clinical management, especially in patients with established lung disease without any other reported risk factors,” first author Valentina Barzon, of the Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, University of Pavia, Italy, and the coauthors of the study wrote.

Many pathological AAT variants causing AAT deficiency (AATD) have the same electrophoretic properties as the normal M variant. This makes it difficult to detect these variants using routine methods.

In the present study, the researchers described a new method that helped them detect the variants, namely, M_wurzburg and M_whitstable.

Read more about the diagnosis of AATD

When they compared the phenotypes of the M_wurzburg proteins (identified by exon 5 sequencing of the SERPINA1 gene) using isoelectric focusing, the researchers saw a particular electrophoretic pattern amenable to M_wurzburg. 

The team then validated the specific phenotyping pattern and was able to detect 16 patients with the M_wurzburg variant among patients who were already tested but not sequenced.

For the detection of the M_whitstable allele, the researchers used intron 4 sequencing of the SERPINA1 gene.

They said it is of great importance to refer patients with established lung disease and no other reported risk factors to expert laboratories since isoelectrophocusing and rapid diagnostic tools are not able to detect rare M-like pathogenic variants. 

“In order to avoid the risk of not identifying patients carrying rare AAT variants, continuous updating of diagnostic algorithms is of chief importance,” they wrote.

Reference

Barzon V, Ottaviani S, Balderacchi AM, et al. Improving the laboratory diagnosis of M-like variants related to alpha1-antitrypsin deficiency. Int J Mol Sci. 2022;23(17):9859. doi:10.3390/ijms23179859