{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:01:10Z","timestamp":1760122870058,"version":"3.37.3"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T00:00:00Z","timestamp":1570147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Alpha-1-antitrypsin (A1AT) deficiency is a hereditary condition caused by mutations in the SERPINA1 gene and associated with lung emphysema and liver disease. Laboratory testing in suspected A1AT deficiency involves quantifying serum A1AT concentration and identification of specific alleles by genotyping and phenotyping. The aim of this report was to present a case of the null allele carrier with consequent genotype\/phenotype\/concentration discrepancies and potential misclassification of the Z variant in a 42-year-old white man presenting with symptoms of chronic obstructive pulmonary disease (COPD).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>Serum A1AT concentration was measured using an immunoturbidimetric assay. A1AT phenotype was determined using isoelectric focusing followed with immunofixation (IEF-IF). Genotyping specifically for the S and Z allele was performed by melting curve analysis using real-time PCR and checked by an alternative PCR-RFLP method. Genotype\/phenotype ambiguity and discrepancy were amended using gene sequencing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Laboratory testing revealed highly reduced A1AT concentration (less than 0.30 g\/L), mild to moderate deficient genotype (Pi*Z allele: M\/Z and Pi*S allele: M\/M) and severe deficient Z homozygous phenotype (Pi ZZ). After repeated sampling, the same discordant results were verified by these tests. Further sequencing revealed two clinically relevant and defective variants: rs199422210 (a rare null allele) and rs28929474 (the Z allele).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Due to inability of genotyping kit probes to detect null\/Z allele combination (which mimics the Pi ZZ phenotype), our patient was misclassified as mild to moderate deficient Pi*MZ heterozygote. In all unclear cases, whole-gene sequencing is highly recommended in order to determine definitive cause of A1AT deficiency.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/labmed\/lmz059","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T11:21:46Z","timestamp":1563967306000},"page":"301-305","source":"Crossref","is-referenced-by-count":1,"title":["\u03b1-1 Antitrypsin Genotype-Phenotype Discrepancy in a 42-Year-Old Man Who Carries the Null-Allele"],"prefix":"10.1093","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1914-7056","authenticated-orcid":false,"given":"Tomislav","family":"Pavi\u010di\u0107","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Medical School University Hospital Sestre Milosrdnice, Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3982-5777","authenticated-orcid":false,"given":"Ivana","family":"\u0106elap","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Medical School University Hospital Sestre Milosrdnice, Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milena","family":"Njegovan","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Medical School University Hospital Sestre Milosrdnice, Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6871-2686","authenticated-orcid":false,"given":"Andrea","family":"Te\u0161ija Kuna","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Medical School University Hospital Sestre Milosrdnice, Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"\u0160tefanovi\u0107","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Medical School University Hospital Sestre Milosrdnice, Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,10,4]]},"reference":[{"issue":"9478","key":"2020050608074513200_CIT0001","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1016\/S0140-6736(05)66781-5","article-title":"\u03b11-antitrypsin deficiency","volume":"365","author":"Stoller","year":"2005","journal-title":"Lancet."},{"issue":"3","key":"2020050608074513200_CIT0002","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1136\/thx.2003.006502","article-title":"\u03b1\u200a1-antitrypsin deficiency. 2: genetic aspects of \u03b1\u200a1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk","volume":"59","author":"DeMeo","year":"2004","journal-title":"Thorax."},{"key":"2020050608074513200_CIT0003","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1053\/rmed.2000.0851","article-title":"Molecular mechanisms of alpha1-antitrypsin null alleles","volume":"94","author":"Lee","year":"2000","journal-title":"Respir Med."},{"issue":"2","key":"2020050608074513200_CIT0004","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1034\/j.1399-0004.2002.620212.x","article-title":"\u03b11-Antitrypsin null alleles: evidence for the recurrence of the L353fsX376 mutation and a novel G\u2013&gt;A transition in position +1 of intron IC affecting normal mRNA splicing","volume":"62","author":"Seixas","year":"2002","journal-title":"Clin Genet."},{"issue":"5","key":"2020050608074513200_CIT0005","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1136\/thx.2003.006510","article-title":"\u03b1\u200a1-antitrypsin deficiency. 3: clinical manifestations and natural history","volume":"59","author":"Needham","year":"2004","journal-title":"Thorax."},{"issue":"2","key":"2020050608074513200_CIT0006","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1203\/01.pdr.0000228350.61496.90","article-title":"Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency","volume":"60","author":"Perlmutter","year":"2006","journal-title":"Pediatr Res."},{"issue":"7","key":"2020050608074513200_CIT0007","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1164\/rccm.168.7.818","article-title":"Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency","volume":"168","author":"American Thoracic Society\/European Respiratory Society Statement","year":"2003","journal-title":"Am J Respir Crit Care Med."},{"issue":"2","key":"2020050608074513200_CIT0008","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/clinchem\/46.2.156","article-title":"Use of two reporter dyes without interference in a single-tube rapid-cycle PCR: \u03b1\u200a1-antitrypsin genotyping by multiplex real-time fluorescence PCR with the LightCycler","volume":"46","author":"von Ahsen","year":"2000","journal-title":"Clin Chem."},{"issue":"9","key":"2020050608074513200_CIT0009","first-page":"761","article-title":"Rapid and simple diagnosis of the two common alpha 1-proteinase inhibitor deficiency alleles Pi*Z and Pi*S by DNA analysis","volume":"34","author":"Braun","year":"1996","journal-title":"Eur J Clin Chem Clin Biochem."},{"issue":"3","key":"2020050608074513200_CIT0010","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0009-8981(81)90452-6","article-title":"Influence of oral contraceptives of differing dosages on \u03b1-1-antitrypsin, \u03b3-glutamyltransferase and alkaline phosphatase","volume":"112","author":"Herbeth","year":"1981","journal-title":"Clin Chim Acta."},{"issue":"5 Pt 1","key":"2020050608074513200_CIT0011","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1164\/ajrccm.159.5.9711004","article-title":"\u03b1\u200a1-antitrypsin genotypes and the acute-phase response to open heart surgery","volume":"159","author":"Sandford","year":"1999","journal-title":"Am J Respir Crit Care Med."},{"issue":"1","key":"2020050608074513200_CIT0012","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1080\/15412555.2017.1401600","article-title":"The effects of inflammation on alpha 1 antitrypsin levels in a national screening cohort","volume":"15","author":"Sanders","year":"2018","journal-title":"COPD."},{"issue":"12","key":"2020050608074513200_CIT0013","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1373\/clinchem.2006.072991","article-title":"Diagnosis of \u03b11-antitrypsin deficiency: an algorithm of quantification, genotyping, and phenotyping","volume":"52","author":"Snyder","year":"2006","journal-title":"Clin Chem."},{"issue":"10","key":"2020050608074513200_CIT0014","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1093\/clinchem\/45.10.1872","article-title":"High-speed detection of the two common \u03b1\u200a1-antitrypsin deficiency alleles Pi*Z and Pi*S by real-time fluorescence PCR and melting curves","volume":"45","author":"Aslanidis","year":"1999","journal-title":"Clin Chem."},{"issue":"6","key":"2020050608074513200_CIT0015","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.rmed.2008.01.009","article-title":"Alpha-1 antitrypsin Null mutations and severity of emphysema","volume":"102","author":"Fregonese","year":"2008","journal-title":"Respir Med."},{"issue":"2","key":"2020050608074513200_CIT0016","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2174\/138920310790848368","article-title":"Genetic variants of \u03b1 1-antitrypsin","volume":"11","author":"Salahuddin","year":"2010","journal-title":"Curr Protein Pept Sci."},{"issue":"1","key":"2020050608074513200_CIT0017","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1710-1492-7-18","article-title":"A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F\/Null phenotype","volume":"7","author":"Ringenbach","year":"2011","journal-title":"Allergy Asthma Clin Immunol."},{"issue":"3","key":"2020050608074513200_CIT0018","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1136\/jmg.2004.023903","article-title":"Prevalence and phenotype of subjects carrying rare variants in the Italian registry for alpha1-antitrypsin deficiency","volume":"42","author":"Ferrarotti","year":"2005","journal-title":"J Med Genet."},{"issue":"5","key":"2020050608074513200_CIT0019","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.trsl.2007.08.001","article-title":"Laboratory diagnosis of alpha1-antitrypsin deficiency","volume":"150","author":"Ferrarotti","year":"2007","journal-title":"Trans Res."}],"container-title":["Laboratory Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/labmed\/article-pdf\/51\/3\/301\/33174929\/lmz059.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/labmed\/article-pdf\/51\/3\/301\/33174929\/lmz059.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T15:10:07Z","timestamp":1588777807000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/labmed\/article\/51\/3\/301\/5580787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,4]]},"references-count":19,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,10,4]]},"published-print":{"date-parts":[[2020,5,6]]}},"URL":"https:\/\/doi.org\/10.1093\/labmed\/lmz059","relation":{},"ISSN":["0007-5027","1943-7730"],"issn-type":[{"type":"print","value":"0007-5027"},{"type":"electronic","value":"1943-7730"}],"subject":[],"published-other":{"date-parts":[[2020,5]]},"published":{"date-parts":[[2019,10,4]]}}}