{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T03:30:19Z","timestamp":1786591819590,"version":"build-2736575974"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":65,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008750","name":"Shanghai Municipal Hospital Development Center","doi-asserted-by":"publisher","award":["SHDC2020CR2058B"],"award-info":[{"award-number":["SHDC2020CR2058B"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["2021R092"],"award-info":[{"award-number":["2021R092"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biol Sex Differ"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>NR5A1<\/jats:italic>\n                      encodes a transcription factor essential for adrenal and gonadal development. Gene variants are a known cause of heterogeneous 46,XY disorders of sex development (DSD), but the mechanisms underlying the phenotypic variability remain unclear. We investigated how different\n                      <jats:italic>NR5A1<\/jats:italic>\n                      variants affect downstream gene regulation and contribute to DSD pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed four naturally occurring\n                      <jats:italic>NR5A1<\/jats:italic>\n                      variants identified in patients with 46,XY DSD\u2014two novel (p.Cys65Ser, p.His310Arg) and two previously reported (p.Cys30Ser, p.Gln329*). We performed protein and transcriptomic analyses to characterize variant effects and identify dysregulated and candidate target genes, validated by qPCR and luciferase assays. Transcriptomic and CUT&amp;Tag analyses focused on the p.Gln329* truncating variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All four variants occurred at conserved residues and resulted in reduced NR5A1 protein expression and impaired nuclear localization upon transfection in HEK293T cells. Transcriptomic analysis using the p.Gln329* variant revealed broad downregulation of genes involved in steroidogenesis, including\n                      <jats:italic>CYP11A1<\/jats:italic>\n                      ,\n                      <jats:italic>STAR<\/jats:italic>\n                      , and\n                      <jats:italic>CYP17A1<\/jats:italic>\n                      . Notably,\n                      <jats:italic>AMHR2<\/jats:italic>\n                      and\n                      <jats:italic>STARD8<\/jats:italic>\n                      were significantly downregulated and showed reduced CUT&amp;Tag signal in variant-transfected cells. Promoter assays confirmed that all variants diminished\n                      <jats:italic>CYP11A1<\/jats:italic>\n                      and\n                      <jats:italic>AMHR2<\/jats:italic>\n                      promoter activity. Only the p.Gln329* variant affected\n                      <jats:italic>STARD8<\/jats:italic>\n                      promoter activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings indicate that\n                      <jats:italic>NR5A1<\/jats:italic>\n                      variants impair protein expression and localization, leading to transcriptional dysregulation of genes involved in steroid hormone biosynthesis and sexual development. Based on analysis of the p.Gln329* truncating variant,\n                      <jats:italic>AMHR2<\/jats:italic>\n                      and\n                      <jats:italic>STARD8<\/jats:italic>\n                      are strong candidate novel downstream targets of NR5A1, offering further insight into the mechanisms driving 46,XY DSD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-026-00939-0","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T02:45:30Z","timestamp":1780973130000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional and transcriptomic insights into 46,XY disorders of sex development associated with NR5A1 gene variants"],"prefix":"10.1186","volume":"17","author":[{"given":"Qingxu","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaolian","family":"Zang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqin","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"939_CR1","doi-asserted-by":"publisher","unstructured":"Ikeda Y, Shen W, Ingraham H, Parker K. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Molecular endocrinology (Baltimore, Md). 1994;8:5:654\u201362; https:\/\/doi.org\/10.1210\/mend.8.5.8058073","DOI":"10.1210\/mend.8.5.8058073"},{"key":"939_CR2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/s0925-4773(99)00123-9","volume":"87","author":"N Hanley","year":"1999","unstructured":"Hanley N, Ball S, Clement-Jones M, Hagan D, Strachan T, Lindsay S, et al. Expression of steroidogenic factor 1 and Wilms\u2019 tumour 1 during early human gonadal development and sex determination. Mech Dev. 1999;87:175\u201380. https:\/\/doi.org\/10.1016\/s0925-4773(99)00123-9.","journal-title":"Mech Dev"},{"issue":"4","key":"939_CR3","doi-asserted-by":"publisher","first-page":"756","DOI":"10.3803\/EnM.2020.402","volume":"35","author":"K Morohashi","year":"2020","unstructured":"Morohashi K, Inoue M, Baba T. Coordination of Multiple Cellular Processes by NR5A1\/Nr5a1. Endocrinol metabolism (Seoul Korea). 2020;35(4):756\u201364. https:\/\/doi.org\/10.3803\/EnM.2020.402.","journal-title":"Endocrinol metabolism (Seoul Korea)"},{"key":"939_CR4","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3390\/ijms21041429","volume":"21","author":"N Emura","year":"2020","unstructured":"Emura N, Wang C, Yang W, Yang W. Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity. Int J Mol Sci. 2020;21:4. https:\/\/doi.org\/10.3390\/ijms21041429.","journal-title":"Int J Mol Sci"},{"key":"939_CR5","doi-asserted-by":"publisher","first-page":"6e68050","DOI":"10.1371\/journal.pone.0068050","volume":"8","author":"K Miyabayashi","year":"2013","unstructured":"Miyabayashi K, Katoh-Fukui Y, Ogawa H, Baba T, Shima Y, Sugiyama N, et al. Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells. PLoS ONE. 2013;8:6e68050. https:\/\/doi.org\/10.1371\/journal.pone.0068050.","journal-title":"PLoS ONE"},{"issue":"1","key":"939_CR6","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1002\/humu.20588","volume":"29","author":"B K\u00f6hler","year":"2008","unstructured":"K\u00f6hler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schr\u00f6der V, et al. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat. 2008;29(1):59\u201364. https:\/\/doi.org\/10.1002\/humu.20588.","journal-title":"Hum Mutat"},{"key":"939_CR7","doi-asserted-by":"publisher","unstructured":"Mazen I, Abdel-Hamid M, Mekkawy M, Bignon-Topalovic J, Boudjenah R, El Gammal M et al. Identification of NR5A1 Mutations and Possible Digenic Inheritance in 46,XY Gonadal Dysgenesis. Sexual development: genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation. 2016;10:3:147\u201351; https:\/\/doi.org\/10.1159\/000445983","DOI":"10.1159\/000445983"},{"key":"939_CR8","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1038\/s41431-018-0202-7","volume":"26","author":"N Camats","year":"2018","unstructured":"Camats N, Fern\u00e1ndez-Cancio M, Aud\u00ed L, Schaller A, Fl\u00fcck C. Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin? Eur J Hum genetics: EJHG. 2018;26:9:1329\u201338. https:\/\/doi.org\/10.1038\/s41431-018-0202-7.","journal-title":"Eur J Hum genetics: EJHG"},{"key":"939_CR9","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1055\/s-0032-1324720","volume":"30","author":"R El-Khairi","year":"2012","unstructured":"El-Khairi R, Achermann J. Steroidogenic factor-1 and human disease. Semin Reprod Med. 2012;30:5. https:\/\/doi.org\/10.1055\/s-0032-1324720.","journal-title":"Semin Reprod Med"},{"key":"939_CR10","doi-asserted-by":"publisher","first-page":"104941","DOI":"10.1016\/j.ebiom.2023.104941","volume":"99","author":"C Kouri","year":"2024","unstructured":"Kouri C, Sommer G, Martinez de Lapiscina I, Elzenaty R, Tack L, Cools M, et al. Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1\/SF-1 variants of sex development. EBioMedicine. 2024;99:104941. https:\/\/doi.org\/10.1016\/j.ebiom.2023.104941.","journal-title":"EBioMedicine"},{"key":"939_CR11","doi-asserted-by":"publisher","first-page":"D330","DOI":"10.1093\/nar\/gky1055","volume":"47","author":"The Gene Ontology Resource","year":"2019","unstructured":"The Gene Ontology Resource. 20 years and still GOing strong. Nucleic Acids Res. 2019;47:D330\u20138. https:\/\/doi.org\/10.1093\/nar\/gky1055.","journal-title":"Nucleic Acids Res"},{"key":"939_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-024-47162-2","volume":"15","author":"H Denis","year":"2024","unstructured":"Denis H, Caroline E, Carlos FL, Ma\u00ebva E, Joelle B-T, Inma G, et al. A conserved NR5A1-responsive enhancer regulates SRY in testis-determination. Nat Commun. 2024;15:1. https:\/\/doi.org\/10.1038\/s41467-024-47162-2.","journal-title":"Nat Commun"},{"issue":"7","key":"939_CR13","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1210\/me.2009-0519","volume":"24","author":"B Schimmer","year":"2010","unstructured":"Schimmer B, White P. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol (Baltimore Md). 2010;24(7):1322\u201337. https:\/\/doi.org\/10.1210\/me.2009-0519.","journal-title":"Mol Endocrinol (Baltimore Md)"},{"issue":"1","key":"939_CR14","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/humu.23916","volume":"41","author":"H Fabbri-Scallet","year":"2020","unstructured":"Fabbri-Scallet H, de Sousa L, Maciel-Guerra A, Guerra-J\u00fanior G, de Mello M. Mutation update for the NR5A1 gene involved in DSD and infertility. Hum Mutat. 2020;41(1):58\u201368. https:\/\/doi.org\/10.1002\/humu.23916.","journal-title":"Hum Mutat"},{"key":"939_CR15","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s12020-021-02883-y","volume":"75","author":"I M\u00f6nig","year":"2022","unstructured":"M\u00f6nig I, Schneidewind J, Johannsen T, Juul A, Werner R, L\u00fcnstedt R, et al. Pubertal development in 46,XY patients with NR5A1 mutations. Endocrine. 2022;75:2. https:\/\/doi.org\/10.1007\/s12020-021-02883-y.","journal-title":"Endocrine"},{"key":"939_CR16","doi-asserted-by":"publisher","first-page":"3148","DOI":"10.1016\/j.ando.2009.02.002","volume":"70","author":"M Doghman","year":"2009","unstructured":"Doghman M, Lalli E. A matter of dosage: SF-1 in adrenocortical development and cancer. Ann Endocrinol. 2009;70:3148\u201352. https:\/\/doi.org\/10.1016\/j.ando.2009.02.002.","journal-title":"Ann Endocrinol"},{"key":"939_CR17","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.mce.2014.10.022","volume":"408","author":"C Ruggiero","year":"2015","unstructured":"Ruggiero C, Doghman M, Lalli E. How genomic studies have improved our understanding of the mechanisms of transcriptional regulation by NR5A nuclear receptors. Mol Cell Endocrinol. 2015;408:138\u201344. https:\/\/doi.org\/10.1016\/j.mce.2014.10.022.","journal-title":"Mol Cell Endocrinol"},{"issue":"4","key":"939_CR18","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1210\/me.2005-0384","volume":"20","author":"T Little","year":"2006","unstructured":"Little T, Zhang Y, Matulis C, Weck J, Zhang Z, Ramachandran A, et al. Sequence-specific deoxyribonucleic acid (DNA) recognition by steroidogenic factor 1: a helix at the carboxy terminus of the DNA binding domain is necessary for complex stability. Mol Endocrinol (Baltimore Md). 2006;20(4):831\u201343. https:\/\/doi.org\/10.1210\/me.2005-0384.","journal-title":"Mol Endocrinol (Baltimore Md)"},{"issue":"2","key":"939_CR19","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1152\/physrev.00019.2018","volume":"99","author":"M Meinsohn","year":"2019","unstructured":"Meinsohn M, Smith O, Bertolin K, Murphy B. The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction. Physiol Rev. 2019;99(2):1249\u201379. https:\/\/doi.org\/10.1152\/physrev.00019.2018.","journal-title":"Physiol Rev"},{"key":"939_CR20","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1530\/eje-13-0965","volume":"170","author":"S Tantawy","year":"2014","unstructured":"Tantawy S, Mazen I, Soliman H, Anwar G, Atef A, El-Gammal M, et al. Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development. Eur J Endocrinol. 2014;170:5. https:\/\/doi.org\/10.1530\/eje-13-0965.","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"939_CR21","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1159\/000448013","volume":"10","author":"H Fabbri","year":"2016","unstructured":"Fabbri H, Ribeiro de Andrade J, Maciel-Guerra A, Guerra-J\u00fanior G, de Mello M. NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations. Sex development: Genet Mol biology Evol Endocrinol Embryol Pathol sex Determ Differ. 2016;10(4):191\u20139. https:\/\/doi.org\/10.1159\/000448013.","journal-title":"Sex development: Genet Mol biology Evol Endocrinol Embryol Pathol sex Determ Differ"},{"key":"939_CR22","doi-asserted-by":"publisher","first-page":"145004","DOI":"10.1016\/j.gene.2020.145004","volume":"760","author":"X Na","year":"2020","unstructured":"Na X, Mao Y, Tang Y, Jiang W, Yu J, Cao L, et al. Identification and functional analysis of fourteen NR5A1 variants in patients with the 46 XY disorders of sex development. Gene. 2020;760:145004. https:\/\/doi.org\/10.1016\/j.gene.2020.145004.","journal-title":"Gene"},{"key":"939_CR23","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/j.cmet.2015.04.010","volume":"21","author":"S Jinn","year":"2015","unstructured":"Jinn S, Brandis K, Ren A, Chacko A, Dudley-Rucker N, Gale S, et al. snoRNA U17 regulates cellular cholesterol trafficking. Cell Metabol. 2015;21:6:855\u201367. https:\/\/doi.org\/10.1016\/j.cmet.2015.04.010.","journal-title":"Cell Metabol"},{"issue":"2","key":"939_CR24","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/9629","volume":"22","author":"J Achermann","year":"1999","unstructured":"Achermann J, Ito M, Ito M, Hindmarsh P, Jameson J. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999;22(2):125\u20136. https:\/\/doi.org\/10.1038\/9629.","journal-title":"Nat Genet"},{"key":"939_CR25","doi-asserted-by":"publisher","unstructured":"Domenice S, Machado A, Ferreira F, Ferraz-de-Souza B, Lerario A, Lin L et al. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals. Birth defects research Part C, Embryo today: reviews. 2016;108:4:309\u201320; https:\/\/doi.org\/10.1002\/bdrc.21145","DOI":"10.1002\/bdrc.21145"},{"key":"939_CR26","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1210\/me.2003-0404","volume":"18","author":"P Jeyasuria","year":"2004","unstructured":"Jeyasuria P, Ikeda Y, Jamin S, Zhao L, De Rooij D, Themmen A, et al. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Molecular endocrinology (Baltimore. Md). 2004;18:7. https:\/\/doi.org\/10.1210\/me.2003-0404.","journal-title":"Md)"},{"key":"939_CR27","doi-asserted-by":"publisher","unstructured":"Ilaslan E, Calvel P, Nowak D, Szarras-Czapnik M, Slowikowska-Hilczer J, Spik A et al. A Case of Two Sisters Suffering from 46,XY Gonadal Dysgenesis and Carrying a Mutation of a Novel Candidate Sex-Determining Gene STARD8 on the X Chromosome. Sexual development: genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation. 2018;12:4:191\u20135; https:\/\/doi.org\/10.1159\/000489692","DOI":"10.1159\/000489692"},{"issue":"7","key":"939_CR28","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1071\/rd17501","volume":"31","author":"J Picard","year":"2019","unstructured":"Picard J, Josso N. Persistent M\u00fcllerian duct syndrome: an update. Reprod Fertil Dev. 2019;31(7):1240\u20135. https:\/\/doi.org\/10.1071\/rd17501.","journal-title":"Reprod Fertil Dev"},{"key":"939_CR29","doi-asserted-by":"publisher","unstructured":"Sotillos S, von der Decken I, Domenech Mercad\u00e9 I, Srinivasan S, Sirokha D, Livshits L, et al. DrosophilaA conserved function of Human DLC3 and Cv-c in testis development. eLife. 2022;11. https:\/\/doi.org\/10.7554\/eLife.82343.","DOI":"10.7554\/eLife.82343"},{"key":"939_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.stemcr.2016.11.010","volume":"8","author":"Y Yan","year":"2016","unstructured":"Yan Y, Ziyi L, Xupeng W, Haolin C, Wenting X, Qi X, et al. Direct Reprogramming of Mouse Fibroblasts toward Leydig-like Cells by Defined Factors. Stem Cell Rep. 2016;8:1. https:\/\/doi.org\/10.1016\/j.stemcr.2016.11.010.","journal-title":"Stem Cell Rep"},{"key":"939_CR31","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1093\/gpbjnl\/qzaf072","volume":"23","author":"E Sisi Z\u5f20, Xu C\u9648","year":"2025","unstructured":"Sisi Z\u5f20, Xu C\u9648 E, J\u91d1 A, W\u738b T, C\u9648 X, Z\u5f20, et al. The GSA Family in 2025: A Broadened Sharing Platform for Multi-omics and Multimodal Data. Genomics Proteom Bioinf. 2025;23:4. https:\/\/doi.org\/10.1093\/gpbjnl\/qzaf072.","journal-title":"Genomics Proteom Bioinf"},{"key":"939_CR32","doi-asserted-by":"publisher","first-page":"0","DOI":"10.1093\/nar\/gkae978","volume":"53","author":"Database Resources of the National Genomics Data Center","year":"2024","unstructured":"Database Resources of the National Genomics Data Center. China National Center for Bioinformation in 2025. Nucleic Acids Res. 2024;53:0. https:\/\/doi.org\/10.1093\/nar\/gkae978.","journal-title":"Nucleic Acids Res"}],"container-title":["Biology of Sex Differences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13293-026-00939-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13293-026-00939-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13293-026-00939-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T03:11:54Z","timestamp":1786590714000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13293-026-00939-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["939"],"URL":"https:\/\/doi.org\/10.1186\/s13293-026-00939-0","relation":{},"ISSN":["2042-6410"],"issn-type":[{"value":"2042-6410","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]},"assertion":[{"value":"13 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committee of Shanghai Children\u2019s Hospital, Shanghai Jiao Tong University (approval number: 2021R092-E01, Shanghai, China). Written informed consent was obtained from all participating patients.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors and participants agree to publication.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"145"}}