{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:03:56Z","timestamp":1765976636187,"version":"3.41.2"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Red cell pyruvate kinase (PK) deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia and the most frequent enzyme abnormality of the glycolytic pathway. To the best of our knowledge, this is the first Korean PK deficiency study that analyzes copy number variation (CNV) using next-generation sequencing (NGS). A 7-year-old girl with jaundice was admitted for evaluation of a persistent hemolytic anemia. The proband appeared chronically ill, showing a yellowish skin color, icteric sclera, hepatomegaly, and splenomegaly on physical examination. Sequence variants and CNV generated from NGS data were estimated to determine if there was a potential genetic cause. As a result, compound heterozygosity in the <jats:italic>PKLR<\/jats:italic> gene for a large exon deletion between exon 3 and exon 9 accompanied with a novel rare p.Gly536Asp variant located on exon 10 was identified as a cause of severe PK deficiency in the proband. The PK activity of the proband had been measured at the time of day 1, 21, and 28 after receiving transfusion to indirectly assume the effect of the transfused blood, and the results were 100.9%, 73.0%, and 48.5%, compared with average of normal controls, respectively. Our report emphasizes the need to perform complete CNV analysis of NGS data and gene dosage assays such as multiplex ligation-dependent probe amplification to evaluate large deletions or duplications\/insertions of the <jats:italic>PKLR<\/jats:italic> gene in patients with suspected PK deficiency.<\/jats:p>","DOI":"10.3389\/fped.2022.1022980","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T16:35:46Z","timestamp":1669912546000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Case report: Compound heterozygosity in PKLR gene with a large exon deletion and a novel rare p.Gly536Asp variant as a cause of severe pyruvate kinase deficiency"],"prefix":"10.3389","volume":"10","author":[{"given":"Minsun","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung Yeob","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Namsu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaehyeon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dal Sik","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joonhong","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong Gon","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/j.1365-2141.2005.05527.x","article-title":"Red cell pyruvate kinase deficiency: molecular and clinical aspects","volume":"130","author":"Zanella","year":"2005","journal-title":"Br J Haematol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"197","DOI":"10.5045\/kjh.2007.42.3.197","article-title":"Hereditary hemolytic anemia in Korea: a retrospective study from 1997 to 2006","volume":"42","author":"Cho","year":"2007","journal-title":"Korean J Hematol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e279","DOI":"10.3346\/jkms.2020.35.e279","article-title":"Epidemiological study of hereditary hemolytic anemia in the Korean pediatric population during 1997-2016: a nationwide retrospective cohort study","volume":"35","author":"Shim","year":"2020","journal-title":"J Korean Med Sci"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1182\/blood-2017-10-810796","article-title":"Clinical spectrum of pyruvate kinase deficiency: data from the pyruvate kinase deficiency natural history study","volume":"131","author":"Grace","year":"2018","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.clinbiochem.2021.02.003","article-title":"Six novel variants in the PKLR gene associated with pyruvate kinase deficiency in Argentinian patients","volume":"91","author":"Milanesio","year":"2021","journal-title":"Clin Biochem"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1038\/bmt.2016.218","article-title":"Hemolytic anemia with null PKLR mutations identified using whole exome sequencing and cured by hematopoietic stem cell transplantation combined with splenectomy","volume":"51","author":"Kim","year":"2016","journal-title":"Bone Marrow Transplant"},{"key":"B7","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1056\/NEJMoa1902678","article-title":"Safety and efficacy of mitapivat in pyruvate kinase deficiency","volume":"381","author":"Grace","year":"2019","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.bcmd.2015.12.009","article-title":"Red blood cell PK deficiency: an update of PK-LR gene mutation database","volume":"57","author":"Canu","year":"2016","journal-title":"Blood Cells Mol Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2218","DOI":"10.3324\/haematol.2019.241141","article-title":"Molecular heterogeneity of pyruvate kinase deficiency","volume":"105","author":"Bianchi","year":"2020","journal-title":"Haematologica"},{"key":"B10","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1159\/000084453","article-title":"A novel homozygous mutation of PKLR gene in a pyruvate-kinase-deficient Korean family","volume":"113","author":"Park-Hah","year":"2005","journal-title":"Acta Haematol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1080\/08880018.2021.1950877","article-title":"Molecular genetic testing enabled the diagnosis of otherwise undiagnosable cases of pyruvate kinase deficiency","volume":"39","author":"Chueh","year":"2022","journal-title":"Pediatr Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/gim.2015.156","article-title":"VisCap: inference and visualization of germ-line copy-number variants from targeted clinical sequencing data","volume":"18","author":"Pugh","year":"2016","journal-title":"Genet Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/ejhg.2017.42","article-title":"Validation of copy number variation analysis for next-generation sequencing diagnostics","volume":"25","author":"Ellingford","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/ajh.25325","article-title":"Addressing the diagnostic gaps in pyruvate kinase deficiency: consensus recommendations on the diagnosis of pyruvate kinase deficiency","volume":"94","author":"Bianchi","year":"2019","journal-title":"Am J Hematol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1073\/pnas.85.6.1792","article-title":"Human liver type pyruvate kinase: complete amino acid sequence and the expression in mammalian cells","volume":"85","author":"Tani","year":"1988","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B18","doi-asserted-by":"publisher","first-page":"8218","DOI":"10.1073\/pnas.88.18.8218","article-title":"CDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (Thr384\u2014Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic Anemia","volume":"88","author":"Kanno","year":"1991","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B19","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.blre.2007.01.001","article-title":"Pyruvate kinase deficiency: the genotype-phenotype association","volume":"21","author":"Zanella","year":"2007","journal-title":"Blood Rev"},{"key":"B20","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1111\/j.1365-2141.2008.07535.x","article-title":"Regulation of iron metabolism through Gdf15 and hepcidin in pyruvate kinase deficiency","volume":"144","author":"Finkenstedt","year":"2009","journal-title":"Br J Haematol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e428","DOI":"10.3324\/haematol.2018.214692","article-title":"Compound heterozygosity in Pklr gene for a previously unrecognized intronic polymorphism and a rare missense mutation as a novel cause of severe pyruvate kinase deficiency","volume":"104","author":"Bagla","year":"2019","journal-title":"Haematologica"},{"key":"B22","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1002\/ajh.25058","article-title":"Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias","volume":"93","author":"Russo","year":"2018","journal-title":"Am J Hematol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.jmoldx.2020.01.007","article-title":"Next-generation sequencing-based diagnosis of unexplained inherited hemolytic anemias reveals wide genetic and phenotypic heterogeneity","volume":"22","author":"Jamwal","year":"2020","journal-title":"J Mol Diagn"},{"key":"B24","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1186\/s13023-020-01425-5","article-title":"Exome sequencing for diagnosis of congenital hemolytic anemia","volume":"15","author":"Mansour-Hendili","year":"2020","journal-title":"Orphanet J Rare Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1080\/17474086.2021.1886919","article-title":"Screening tools for hereditary hemolytic anemia: new concepts and strategies","volume":"14","author":"Fermo","year":"2021","journal-title":"Expert Rev Hematol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/978-1-4939-8666-8_9","article-title":"Detection of CNVs in NGS data using VS-CNV","volume":"1833","author":"Fortier","year":"2018","journal-title":"Methods Mol Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.mrrev.2019.02.005","article-title":"Free-access copy-number variant detection tools for targeted next-generation sequencing data","volume":"779","author":"Roca","year":"2019","journal-title":"Mutat Res Rev Mutat Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1002\/ajh.25753","article-title":"Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency","volume":"95","author":"Bianchi","year":"2020","journal-title":"Am J Hematol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3324\/%25x","article-title":"Severe hemolytic anemia in a Vietnamese family, associated with novel mutations in the gene encoding for pyruvate kinase","volume":"90","author":"Costa","year":"2005","journal-title":"Haematologica"},{"key":"B30","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1179\/102453311(13127324303317","article-title":"First reported case of prenatal diagnosis for pyruvate kinase deficiency in a Chinese family","volume":"16","author":"So","year":"2011","journal-title":"Hematology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"23807","DOI":"10.1074\/jbc.M202107200","article-title":"Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia","volume":"277","author":"Valentini","year":"2002","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.bcmd.2013.05.006","article-title":"Molecular and clinical heterogeneity in pyruvate kinase deficiency in India","volume":"51","author":"Warang","year":"2013","journal-title":"Blood Cells Mol Dis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1111\/ijlh.12610","article-title":"Molecular basis of pyruvate kinase deficiency among Tunisians: description of new mutations affecting coding and noncoding regions in the PKLR gene","volume":"39","author":"Jaouani","year":"2017","journal-title":"Int J Lab Hematol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.bjhh.2017.08.007","article-title":"Novel mutations associated with pyruvate kinase deficiency in Brazil","volume":"40","author":"Svidnicki","year":"2018","journal-title":"Rev Bras Hematol Hemoter"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1111\/bjh.16724","article-title":"The pyruvate kinase (PK) to hexokinase enzyme activity ratio and erythrocyte PK protein level in the diagnosis and phenotype of PK deficiency","volume":"192","author":"Al-Samkari","year":"2021","journal-title":"Br J Haematol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3847","DOI":"10.1182\/blood.V89.10.3847","article-title":"Molecular characterization of PK-LR gene in pyruvate kinase-deficient Italian patients","volume":"89","author":"Zanella","year":"1997","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1373\/jalm.2019.029579","article-title":"Development of an automated enzymatic method to quantify pyruvate kinase in red blood cells","volume":"5","author":"Lu","year":"2020","journal-title":"J Appl Lab Med"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.1022980\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T16:35:50Z","timestamp":1669912550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.1022980\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,1]]},"references-count":37,"alternative-id":["10.3389\/fped.2022.1022980"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.1022980","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2022,12,1]]},"article-number":"1022980"}}