PiComplutense (p.Pro393Thr): A novel SERPINA1 variant in Alpha-1 antitrypsin deficiency identified in two siblings

Alpha-1 antitrypsin deficiency (AATD) is a common yet underrecognized genetic condition that predisposes to early-onset emphysema and liver disease. Diagnostic algorithms typically target frequent alleles (S and Z), potentially missing rare variants in patients with discordant phenotypes.

We report two biologically related individuals (sisters) referred to our respiratory outpatient clinic after persistently low serum AAT levels despite an initial Pi∗MZ genotype. Longitudinal clinical, functional, and radiological evaluation revealed divergent trajectories: Case 1 remained asymptomatic with stable lung function and normal imaging, while Case 2 developed mild emphysema and progressive airflow obstruction. Serum AAT levels were markedly reduced in both patients (60-61 mg/dL and 57-50 mg/dL, respectively; reference range: 90-200 mg/dL). Given the phenotype-genotype discordance, full-gene sequencing was performed and identified a previously unreported SERPINA1 variant, c.1177C > A (p.Pro393Thr), in trans, combined with the Z allele, in both sisters.

Codon 393 is functionally relevant, as shown by the known pathogenic Würzburg variant (p.Pro393Ser). The location of the novel variant within beta-sheet C, its trans configuration with Z, the associated biochemical phenotype, and segregation in two related individuals support its likely pathogenicity. We propose the designation PiComplutense for this mutation.

These cases highlight the diagnostic value of extended SERPINA1 sequencing in patients with biochemical-genotypic discordance. Although the most frequent deficient alleles are S and Z, we should think about possible rare variants when discordance exists. There is a need to improve early detection, refine risk assessment and support personalised clinical management.