{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:15:45Z","timestamp":1787314545770,"version":"build-2736575974"},"reference-count":24,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hereditary hemolytic anemias (HHA) comprise a heterogeneous group of disorders resulting from defective red blood cell (RBC) cytoskeleton, RBC enzyme deficiencies, and hemoglobin (Hb) synthesis disorders such as thalassemia or sideroblastic anemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Our hemolytic anemia diagnostic next\u2010generation sequencing (NGS) panel includes 28 genes encoding RBC cytoskeletal proteins, membrane transporter, RBC enzymes, and certain bilirubin metabolism genes. The panel covers the complete coding region of these genes, splice junctions, and, wherever appropriate, deep intronic or regulatory regions are also included. Four hundred fifty\u2010six patients with unexplained hemolytic anemia were evaluated using our NGS panel between 2015 and 2019.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified pathogenic\/likely pathogenic variants in 111\/456 (24%) patients that were responsible for the disease phenotype (e.g., moderate to severe hemolytic anemia and hyperbilirubinemia). Approximately 40% of the mutations were novel. As expected, 45\/456 (10%) patients were homozygous for the promoter polymorphism in the\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      gene, A(TA)\n                      <jats:sub>7<\/jats:sub>\n                      TAA (\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      *28). 8\/45 homozygous\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      *28 cases were associated with additional pathogenic mutations causing hemolytic anemia, likely exacerbating hyperbilirubinemia. The most common mutated genes were membrane cytoskeleton genes\n                      <jats:italic>SPTA1,<\/jats:italic>\n                      and\n                      <jats:italic>SPTB<\/jats:italic>\n                      , followed by\n                      <jats:italic>PKLR.<\/jats:italic>\n                      Complex interactions between SPTA1 low expression alleles\n                      <jats:italic>,<\/jats:italic>\n                      alpha\u2010LELY and alpha\u2010LEPRA alleles, and intragenic SPTA1 variants were associated with hereditary pyropoikilocytosis and autosomal recessive hereditary spherocytosis in 23\/111 patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results demonstrate that hemolytic anemia is underscored by complex molecular interactions of previously known and novel mutations in RBC cytoskeleton\/enzyme genes, and therefore, NGS should be considered in all patients with clinically unexplained hemolytic anemia and in neonates with hyperbilirubinemia. Moreover, low expression alleles alpha\u2010LELY and alpha\u2010LEPRA should be included in all targeted HHA panels.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ejh.13951","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T08:14:01Z","timestamp":1677226441000},"page":"688-695","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Clinical utility of targeted next\u2010generation sequencing panel in routine diagnosis of hereditary hemolytic anemia: A national reference laboratory experience"],"prefix":"10.1111","volume":"110","author":[{"given":"Archana M.","family":"Agarwal","sequence":"first","affiliation":[{"name":"Department of Pathology University of Utah Health and ARUP Laboratories  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1304-2843","authenticated-orcid":false,"given":"Valarie","family":"McMurty","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Utah Health and ARUP Laboratories  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam L.","family":"Clayton","sequence":"additional","affiliation":[{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashini","family":"Bolia","sequence":"additional","affiliation":[{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0806-5661","authenticated-orcid":false,"given":"N. Scott","family":"Reading","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Utah Health and ARUP Laboratories  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah USA"},{"name":"Department of Internal Medicine, Hematology Division University of Utah Health  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coumarane","family":"Mani","sequence":"additional","affiliation":[{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6531-3225","authenticated-orcid":false,"given":"Jay L.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Utah Health and ARUP Laboratories  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Rets","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Utah Health and ARUP Laboratories  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.613559"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2013.04.003"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/ijlh.12657"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.5045\/br.2017.52.2.84"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.16126"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12070958"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2012.01.001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2007.01.001"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2116634"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-11-753525"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2015.1.392"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/ijlh.13014"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199511023331802"},{"key":"e_1_2_9_15_1","unstructured":"LiH.Aligning Sequence Reads Clone Sequences and Assembly Contigs With BWA\u2010MEM; 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