PMID- 37071847 OWN - NLM STAT- MEDLINE DCOM- 20230904 LR - 20231011 IS - 1535-4989 (Electronic) IS - 1044-1549 (Linking) VI - 69 IP - 3 DP - 2023 Sep TI - Comprehensive Clinical Diagnostic Pipelines Reveal New Variants in Alpha-1 Antitrypsin Deficiency. PG - 355-366 LID - 10.1165/rcmb.2022-0470OC [doi] AB - Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed disorder associated with mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT). Severe AATD can manifest as pulmonary emphysema and progressive liver disease. Besides the most common pathogenic variants S (E264V) and Z (E342K), many rarer genetic variants of AAT have been found in patients and in the general population. Here we report a panel of new SERPINA1 variants, including 4 null and 16 missense alleles, identified among a cohort of individuals with suspected AATD whose phenotypic follow-up showed inconclusive or atypical results. Because the pathogenic significance of the missense variants was unclear purely on the basis of clinical data, the integration of computational, biochemical, and cellular studies was used to define the associated risk of disease. Established pathogenicity predictors and structural analysis identified a panel of candidate damaging mutations that were characterized by expression in mammalian cell models. Polymer formation, intracellular accumulation, and secretory efficiency were evaluated experimentally. Our results identified two AAT mutants with a Z-like polymerogenic severe deficiency profile (S(milano) and M(campolongo)) and three milder variants (X(sarezzo), P(dublin), and C(tiberias)). Overall, the experimentally determined behavior of the variants was in agreement with the pathogenicity scores of the REVEL (an ensemble method for predicting the pathogenicity of rare missense variants) predictor, supporting the utility of this bioinformatic tool in the initial assessment of newly identified amino acid substitutions of AAT. Our study, in addition to describing 20 new SERPINA1 variants, provides a model for a multidisciplinary approach to classification of rare AAT variants and their clinical impact on individuals with rare AATD genotypes. FAU - Ottaviani, Stefania AU - Ottaviani S AUID- ORCID: 0000-0002-2039-230X AD - Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Unita Operativa Complessa Pneumologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. FAU - Bartoli, Giulia AU - Bartoli G AUID- ORCID: 0000-0001-8772-1852 AD - Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. FAU - Carroll, Tomas P AU - Carroll TP AUID- ORCID: 0000-0002-0418-1641 AD - alpha-1 Foundation Ireland, Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin, Ireland. FAU - Gangemi, Fabrizio AU - Gangemi F AUID- ORCID: 0000-0001-9389-651X AD - Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. FAU - Balderacchi, Alice M AU - Balderacchi AM AUID- ORCID: 0000-0003-0714-1087 AD - Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Unita Operativa Complessa Pneumologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. FAU - Barzon, Valentina AU - Barzon V AUID- ORCID: 0000-0003-1582-6887 AD - Department of Internal Medicine and Therapeutics, Pulmonology Unit, University of Pavia, Pavia, Italy. FAU - Corino, Alessandra AU - Corino A AD - Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Unita Operativa Complessa Pneumologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. FAU - Piloni, Davide AU - Piloni D AUID- ORCID: 0000-0002-7275-4229 AD - Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Unita Operativa Complessa Pneumologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. FAU - McElvaney, Noel G AU - McElvaney NG AUID- ORCID: 0000-0002-0152-4370 AD - alpha-1 Foundation Ireland, Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin, Ireland. FAU - Corsico, Angelo G AU - Corsico AG AUID- ORCID: 0000-0002-8716-4694 AD - Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Unita Operativa Complessa Pneumologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. AD - Department of Internal Medicine and Therapeutics, Pulmonology Unit, University of Pavia, Pavia, Italy. AD - European Reference Network on Rare Respiratory Diseases (ERN-LUNG); and. FAU - Irving, James A AU - Irving JA AUID- ORCID: 0000-0003-3204-6356 AD - University College London Respiratory, Rayne Institute and the Institute of Structural and Molecular Biology, University College London, London, United Kingdom. FAU - Fra, Annamaria AU - Fra A AUID- ORCID: 0000-0002-4327-3004 AD - Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. FAU - Ferrarotti, Ilaria AU - Ferrarotti I AUID- ORCID: 0000-0003-4892-4192 AD - Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Unita Operativa Complessa Pneumologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. AD - Department of Internal Medicine and Therapeutics, Pulmonology Unit, University of Pavia, Pavia, Italy. AD - European Reference Network on Rare Respiratory Diseases (ERN-LUNG); and. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 8917225 SB - IM MH - Humans MH - *alpha 1-Antitrypsin Deficiency/diagnosis/genetics MH - Genotype MH - Mutation/genetics MH - *Pulmonary Emphysema MH - Mutation, Missense/genetics OTO - NOTNLM OT - SERPINA1 rare variants OT - alpha-1 antitrypsin polymers OT - pathogenicity predictions OT - serpinopathies OT - serpins EDAT- 2023/04/18 18:41 MHDA- 2023/09/04 06:42 CRDT- 2023/04/18 16:23 PHST- 2023/09/04 06:42 [medline] PHST- 2023/04/18 18:41 [pubmed] PHST- 2023/04/18 16:23 [entrez] AID - 10.1165/rcmb.2022-0470OC [doi] PST - ppublish SO - Am J Respir Cell Mol Biol. 2023 Sep;69(3):355-366. doi: 10.1165/rcmb.2022-0470OC.