Clinical implications of a novel SERPINA1 variant c.236 T > A: Challenges in characterizing new rare alpha-1 antitrypsin mutations

Abstract

Severe alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition characterized by low levels of alpha-1 antitrypsin (AAT), leading to progressive lung and/or liver disease. Most severe cases are linked to the Z allele (c.1096G > A (p.Glu366Lys)) of the SERPINA1 gene but characterizing patients with rare mutations remains challenging. This case report discusses the clinical significance of a novel SERPINA1 variant, c.236 T > A (p.Val79Glu; ClinVar accession SCV007334878), and the challenges in profiling such cases. Two male siblings carried both the common Z allele mutation and the novel exon 2 mutation. Despite genetic similarities, their clinical courses diverged. The older brother, a 66-year-old patient, presented with very severe airflow obstruction (GOLD stage IV) and an AAT level of 0.32 g/L. After years of pharmacologic treatment and endoscopic lung volume reduction, his condition worsened, requiring a double lung transplant. In contrast, the younger brother, currently 58 years old, was diagnosed through family screening and had an AAT level of 0.4 g/L. His condition progressed to panlobular basal emphysema accompanied by bronchopathy and mild bronchiectasis, managed with pharmacologic therapy. Both siblings had a history of smoking, potentially influencing their clinical outcomes. This case highlights the complexity of assessing rare SERPINA1 mutations due to underlying biochemical complexities, genetic variability, and diagnostic limitations. It underscores the importance of combining biochemical analysis of variant AAT proteins with clinical evaluation to better understand disease expression, the value of genetic screening in family members, and the need for personalized clinical management to support timely and appropriate therapeutic interventions.