{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:55:17Z","timestamp":1791273317271,"version":"4.1.0"},"reference-count":17,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82000189"],"award-info":[{"award-number":["82000189"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270203"],"award-info":[{"award-number":["82270203"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Case Reports"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    X\u2010linked sideroblastic anemia (XLSA), caused by pathogenic variants in\n                    <jats:italic>ALAS2<\/jats:italic>\n                    , typically presents as microcytic anemia in males. However, heterozygous females occasionally exhibit an atypical macrocytic phenotype, often leading to diagnostic ambiguity and confusion with nutritional anemias or myelodysplastic syndromes. This study aims to characterize a novel\n                    <jats:italic>ALAS2<\/jats:italic>\n                    variant and explore the possible mechanisms underlying macrocytosis in a female patient. We analyzed a 15\u2010year\u2010old female with an 8\u2010year history of refractory macrocytic anemia. Diagnostic evaluations included hematological profiling, iron metabolism studies, and bone marrow examination. Whole\u2010exome sequencing (WES) was employed to identify genetic variants, followed by Sanger validation. Protein structural modeling was performed using AlphaFold 3. The patient presented with severe macrocytic anemia, iron overload, and borderline folate status despite supplementation. WES identified a novel frameshift variant in\n                    <jats:italic>ALAS2<\/jats:italic>\n                    , c.1277dupT (p.M426Ifs*66), which supported the diagnosis of atypical XLSA. Structural modeling suggested that this variant alters the C\u2010terminal region and may affect the conformation of the catalytic site, including the spatial configuration around Lys391, potentially impairing enzymatic function. Additional variants in\n                    <jats:italic>DHX34<\/jats:italic>\n                    ,\n                    <jats:italic>FANCI<\/jats:italic>\n                    , and\n                    <jats:italic>BRIP1<\/jats:italic>\n                    were also identified, although their potential contributions to the phenotype remain uncertain because functional evidence is lacking. In conclusion, we identified a novel, predicted loss\u2010of\u2010function variant in\n                    <jats:italic>ALAS2<\/jats:italic>\n                    associated with early\u2010onset macrocytic XLSA. Macrocytosis in this case may reflect a proposed \u201chigh\u2010turnover\u201d failure involving intramedullary attrition of mutant clones and stress\u2010induced premature maturation of wild\u2010type clones; however, this mechanism remains speculative. Secondary nutrient depletion and additional genetic variants may also contribute, although their roles require further validation. This case underscores the value of genomic sequencing in resolving atypical, refractory anemias in female patients and preventing long\u2010term misdiagnosis.\n                  <\/jats:p>","DOI":"10.1002\/ccr3.73529","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:51:16Z","timestamp":1789645876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Severe Macrocytic Anemia Associated With a Novel\n                    <scp>\n                      <i>ALAS2<\/i>\n                    <\/scp>\n                    Mutation: A Case Report and Literature Review"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4574-6551","authenticated-orcid":false,"given":"Haodong","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kefeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102018\u201008\u2010815951"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2018.08.008"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600792"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2014.04.008"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185\u2010010\u20100688\u20104"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.41.482.740"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.13.4363"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102002\u201006\u20101623"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185\u2010016\u20101949\u20107"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277\u2010017\u20103106\u20107"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/mph.0000000000000864"},{"key":"e_1_2_13_13_1","first-page":"1261","article-title":"Onset of X\u2010Linked Sideroblastic Anemia in the Fourth Decade","volume":"89","author":"Cortes\u00e3o E.","year":"2004","journal-title":"Haematologica"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024024475"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201095590\u2010x"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.29309"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2006.04.003"}],"container-title":["Clinical Case 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