Sara Ylli

An integrated pipeline for characterization and reclassification of rare SERPINA1 variants

Background:

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by mutations in the SERPINA1 gene. Besides the common S (p.E288V) and Z (p.E366K) alleles, numerous rare SERPINA1 variants have been identified in both affected individuals and the general population. 
These variants account for a clinically relevant proportion of AATD cases, with data from the Italian Registry showing that more than 21% of patients with severe AATD carry at least one rare pathogenic SERPINA1 variant.

Rare SERPINA1 variants may impair protein folding, secretion, intracellular retention, polymer formation, structural stability, and anti-protease activity. Their molecular effects may result in highly heterogeneous pulmonary and hepatic manifestations, making clinical interpretation particularly challenging. Consequently, many rare SERPINA1 variants are currently classified as variants of uncertain significance (VUS), while growing evidence suggests that some variants previously considered benign may have been misclassified.

Accurate classification of rare SERPINA1 variants is essential for improving diagnosis, risk stratification, and clinical decision-making. Misclassification may lead to delayed diagnosis, inappropriate patient monitoring, and missed opportunities for early therapeutic intervention. 

Aim:

The aim of this project is to improve the characterization and clinical interpretation of 25 selected rare SERPINA1 variants through a comprehensive multidisciplinary pipeline. We will reassess each variant using genetic analysis, computational prediction, structural modelling, and functional studies to define its molecular behaviour and pathogenic potential. The integration of experimental results with clinical, biochemical, and genetic data will enable the evidence-based reclassification of rare SERPINA1 variants and provide a more accurate distinction between benign, pathogenic, and currently uncertain variants. The results will improve diagnosis, patient stratification, and personalized clinical management in AATD.

This project will be carried out in collaboration with UCL Respiratory and the Institute of Structural and Molecular Biology, University College London under the supervision of Prof. David Lomas and Prof. James Irving.
 

Biography

Sara Ylli obtained a Bachelor’s Degree in Biological Sciences from the University of Piemonte Orientale and a Master’s Degree in Experimental and Applied Biology from the University of Pavia, completed in 2023. She is currently enrolled in the Specialization School in Clinical Pathology and Clinical Biochemistry. She works as a junior researcher at the Centre for the Diagnosis of Alpha-1 Antitrypsin Deficiency coordinated by Prof. Ilaria Ferrarotti, at Fondazione IRCCS Policlinico San Matteo in Pavia, where she contributes to diagnostic activities and basic/clinical research projects focused on Alpha-1 Antitrypsin Deficiency.