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      Clinical presentations of four patients with rare Alpha 1 Antitrypsin variants identified in a single US center

      case-report

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          Abstract

          Alpha 1 Antitrypsin Deficiency (AATD) is a rare condition primarily associated with lung complications and liver disease. As disease symptoms are similar to those in other respiratory conditions, patients generally experience long delays before receiving an accurate diagnosis and treatment. AATD results from mutations in the SERPINA1 gene that encodes Alpha 1 Antitrypsin (AAT). Over 500 single-nucleotide variants have been reported in mutation databases; however, there is increasing interest in the clinical significance of rare and novel SERPINA1 variants. In this case series of four patients from a single US center, next-generation sequencing (NGS) was used to guide AATD diagnosis. Four distinct rare variants of SERPINA1 (P289S; I50N; E204K; H262Y) were identified, three of which were found in patients with advanced chronic obstructive pulmonary disease (COPD)/emphysema. Computational modeling predicted these mutations to have potentially deleterious effects, a finding supported by AAT levels that were comparable with those seen in individuals heterozygous for the most common deficiency allele (PI*MZ). The remaining mutation (E204K) was found in a patient with a cerebral aneurysm; potential links between SERPINA1 variants and neurological conditions, such as cerebral aneurysm and arterial dissections, have been previously reported in individuals with heterozygous AATD phenotypes (PI*MS and PI*MZ). Novel and rare variants, often not detected by basic AATD diagnostic tests, have the potential to contribute to the development of COPD and emphysema. Detection of these variants can be enhanced by NGS, and modeling techniques can help determine if variants are pathogenic, thereby enabling a quicker, more accurate AATD diagnosis.

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          Most cited references24

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

            The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.
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              American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency.

              , (2003)
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                Author and article information

                Contributors
                Journal
                Respir Med Case Rep
                Respir Med Case Rep
                Respiratory Medicine Case Reports
                Elsevier
                2213-0071
                20 January 2021
                2021
                20 January 2021
                : 32
                : 101345
                Affiliations
                [1]Lewis Katz School of Medicine at Temple University, Department of Thoracic Surgery and Medicine, Medicine Education and Research Building (MERB), 3500 N. Broad Street, Philadelphia, PA, 19140, USA
                Article
                S2213-0071(21)00007-1 101345
                10.1016/j.rmcr.2021.101345
                7848626
                33552892
                92e5e5c4-c790-4fbf-b7d0-7791bcd5b311
                © 2021 Published by Elsevier Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 23 June 2020
                : 15 December 2020
                : 13 January 2021
                Categories
                Case Report

                alpha 1 antitrypsin,alpha 1 antitrypsin deficiency,diagnostic tests,mutation,novel variants,serpina1,aat, alpha 1 antitrypsin,aatd, alpha 1 antitrypsin deficiency,cidp, chronic inflammatory demyelinating polyneuropathy,copd, chronic obstructive pulmonary disease,ct, computed tomography,fev1, forced expiratory volume in 1 s,fvc, forced vital capacity,ief, isoelectric focusing,ngs, next-generation sequencing,pcr, polymerase chain reaction

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