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

Background: 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. Case presentation: 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. Discussion: 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. Conclusion: 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.