A new SERPINA1 null allele of the PI*S-plus type: PI*Q0.

Introduction: Certain variants in the SERPINA1 gene cause Alpha-1 antitrypsin deficiency (AATD). Null SERPINA1 alleles result in the full absence of circulating AAT, which increases the severity of AATD-related respiratory illnesses. PI*S-plus alleles are the combination in cis of the PI*S allele with another variant that confers more deleterious features to the haplotype.

Methods: A 51-year-old woman with respiratory symptoms and low serum AAT level (51.6 mg/dl; 9.9 µmol/L) was genotyped by real-time PCR and by standard PCR coupled to Sanger sequencing. AAT phenotype was determined by isoelectric focusing. Haplotype phasing was performed using long-read sequencing. SERPINA1 expression was analyzed by RT-PCR.

Results: Despite the patient was heterozygous for the S variant, exhibited a PiM phenotype. Genetic analysis revealed a heterozygous 8-bp duplication (c.250_257dup) in SERPINA1 exon 2, causing a frameshift in the coding region and the appearance of a premature stop codon (p.Met87Profs*21). Long-read sequencing revealed that this variant was found in cis with the S variant, yielding a novel PI*S-plus null allele, designated PI*Q0. RNA analysis showed the absence of transcripts from this allele, indicating degradation via nonsense-mediated mRNA decay.

Conclusion: PI*Q0 is a novel PI*S-plus null allele causing AATD through degradation of SERPINA1 mRNA. Our finding highlights the importance of combining standard genotyping and haplotype reconstruction for accurate AATD diagnosis, especially when a compound heterozygous for deleterious variants is detected.