{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:00:13Z","timestamp":1787324413913,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016062","name":"Stichting Metakids","doi-asserted-by":"publisher","award":["UMD-ZOE-2022-012"],"award-info":[{"award-number":["UMD-ZOE-2022-012"]}],"id":[{"id":"10.13039\/100016062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016062","name":"Stichting Metakids","doi-asserted-by":"publisher","award":["03-004-2021-T045"],"award-info":[{"award-number":["03-004-2021-T045"]}],"id":[{"id":"10.13039\/100016062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"United for Metabolic Diseases","award":["UMD-ZOE-2022-012"],"award-info":[{"award-number":["UMD-ZOE-2022-012"]}]},{"name":"United for Metabolic Diseases","award":["03-004-2021-T045"],"award-info":[{"award-number":["03-004-2021-T045"]}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"publisher","award":["UMD-ZOE-2022-012"],"award-info":[{"award-number":["UMD-ZOE-2022-012"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"publisher","award":["03-004-2021-T045"],"award-info":[{"award-number":["03-004-2021-T045"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Persistent splenomegaly, often an incidental finding, can originate from a number of inherited metabolic disorders (IMDs). Variants of APOE are primarily known as risk factors in terms of cardiovascular disease; however, severe dysfunction of APOE can result in a disease phenotype with considerable overlap with lysosomal storage disorders (LSDs), including splenomegaly and gross elevation of N-palmitoyl-O-phosphocholine-serine (PPCS). Methods: A case study (deep phenotyping, genetic and FACS analysis) and literature study was conducted. Results: The index patient, with a family history of early-onset cardiovascular disease, presented with splenic infarctions in a grossly enlarged spleen. The identified genetic cause was homozygosity for two APOE variants (c.604C&gt;T, p.(Arg202Cys) and c.512G&gt;A, p.(Gly171Asp); \u03b51\/\u03b51), resulting in a macrophage storage phenotype resembling an LSD that was also present in the brother of the index patient. A FACS analysis of the circulating monocytes showed increased lipid content and the expression of activation markers (CD11b, CCR2, CD36). This activated state enhances lipoprotein intake, which eventually converts these monocytes\/macrophages into foam cells, accumulating in tissues (e.g., spleen and vascular wall). A literature search identified seven individuals with splenomegaly caused by APOE variants (deletion of leucine at position 167). The combined data from all patients identified male gender, splenectomy and obesity as potential modifiers determining the severity of the phenotype (i.e., degree of triglyceride increase in plasma and\/or spleen size). Symptoms are (partially) reversible by lipid-lowering medication and energy restricted diets and splenectomy is contra-indicated. Conclusions: Inherited dyslipidemic splenomegaly caused by disruptive APOE variants should be included in the differential diagnoses of unexplained splenomegaly with abnormal lipid profiles. A plasma lipid profile consistent with dysbetalipoproteinemia is a diagnostic biomarker for this IMD.<\/jats:p>","DOI":"10.3390\/genes16030289","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T04:28:18Z","timestamp":1740716898000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inherited Dyslipidemic Splenomegaly: A Genetic Macrophage Storage Disorder Caused by Disruptive Apolipoprotein E (APOE) Variants"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-942X","authenticated-orcid":false,"given":"Elise A.","family":"Ferreira","sequence":"first","affiliation":[{"name":"Department of Paediatrics, Emma Children\u2019s Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"United for Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4864-9346","authenticated-orcid":false,"given":"Machteld M.","family":"Oud","sequence":"additional","affiliation":[{"name":"United for Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8619-1511","authenticated-orcid":false,"given":"Saskia N.","family":"van der Crabben","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam Reproduction & Development, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Versloot","sequence":"additional","affiliation":[{"name":"Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M. I.","family":"Goorden","sequence":"additional","affiliation":[{"name":"Center for Lysosomal and Metabolic Diseases, Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Clinical Chemistry, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara D. M.","family":"van Karnebeek","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Emma Children\u2019s Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"United for Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam Reproduction & Development, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9983-6614","authenticated-orcid":false,"given":"Jeffrey","family":"Kroon","sequence":"additional","affiliation":[{"name":"Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, 1105 AZ Amsterdam, The Netherlands"},{"name":"Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium"},{"name":"Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9934-6831","authenticated-orcid":false,"given":"Mirjam","family":"Langeveld","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Amsterdam UMC, Research Institute Gastroenterology, Endocrinology & Metabolism (AGEM), University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.jacl.2013.09.003","article-title":"Inherited lipemic splenomegaly and the spectrum of apolipoprotein E p.Leu167del mutation phenotypic variation","volume":"7","author":"Okorodudu","year":"2013","journal-title":"J. Clin. Lipidol."},{"key":"ref_2","unstructured":"Rajkumar, V., and Dumpa, V. (2023). Lysosomal Storage Disease. StatPearls, StatPearls Publishing."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., Levade, T., Astudillo, L., Serratrice, J., and Brassier, A. (2017). A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020441"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ymgme.2017.12.431","article-title":"Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature","volume":"123","author":"Goorden","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/jimd.12595","article-title":"Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation","volume":"46","author":"Chang","year":"2023","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s10545-017-0131-6","article-title":"Next-generation metabolic screening: Targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients","volume":"41","author":"Coene","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Haijes, H.A., Willemsen, M., Van der Ham, M., Gerrits, J., Pras-Raves, M.L., Prinsen, H., Van Hasselt, P.M., De Sain-van der Velden, M.G.M., Verhoeven-Duif, N.M., and Jans, J.J.M. (2019). Direct Infusion Based Metabolomics Identifies Metabolic Disease in Patients\u2019 Dried Blood Spots and Plasma. Metabolites, 9.","DOI":"10.3390\/metabo9010012"},{"key":"ref_8","first-page":"4354","article-title":"Familial splenomegaly: Macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (\u0394149 Leu)]","volume":"85","author":"Nguyen","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1172\/JCI111287","article-title":"A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1","volume":"73","author":"Weisgraber","year":"1984","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13421","DOI":"10.1016\/S0021-9258(17)36849-7","article-title":"Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia","volume":"269","author":"Ji","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1016\/S0022-2275(20)32417-2","article-title":"Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes","volume":"40","author":"Mahley","year":"1999","journal-title":"J. Lipid Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1373\/clinchem.2007.097139","article-title":"An unusual case of severe hypertriglyceridemia and splenomegaly","volume":"54","author":"Rahalkar","year":"2008","journal-title":"Clin. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.pcad.2016.07.007","article-title":"Type III Hyperlipoproteinemia: Still Worth Considering?","volume":"59","author":"Blum","year":"2016","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eaaz4564","DOI":"10.1126\/scitranslmed.aaz4564","article-title":"APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia","volume":"13","author":"Sienski","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/BF02436763","article-title":"Genotyping of a patient homozygous for a rare apolipoprotein E1 [Gly127\u2192Asp; Arg158\u2192Cys] (Weisgraber allele)","volume":"18","author":"Iron","year":"1995","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0022-2275(20)42740-3","article-title":"Normolipemic dysbetalipoproteinemia and hyperlipoproteinemia type III in subjects homozygous for a rare genetic apolipoprotein E variant (apoE1)","volume":"31","author":"Steinmetz","year":"1990","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0021-9150(93)90028-S","article-title":"Rare apolipoprotein E variant identified in a patient with type III hyperlipidaemia","volume":"99","author":"Wenham","year":"1993","journal-title":"Atherosclerosis"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kapellos, T.S., Bonaguro, L., Gemund, I., Reusch, N., Saglam, A., Hinkley, E.R., and Schultze, J.L. (2019). Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02035"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"566","DOI":"10.7326\/L15-5144-2","article-title":"The PRISMA Extension Statement","volume":"163","author":"Hutton","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_20","first-page":"e123","article-title":"Preferred reporting items for systematic reviews and meta-analyses: The PRISMA Statement","volume":"3","author":"Moher","year":"2009","journal-title":"Open Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1038\/sj.ejhg.5201480","article-title":"Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation","volume":"13","author":"Faivre","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/cge.14185","article-title":"Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene","volume":"102","author":"Heidemann","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tippett, E., Cheng, W.J., Westhorpe, C., Cameron, P.U., Brew, B.J., Lewin, S.R., Jaworowski, A., and Crowe, S.M. (2011). Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019968"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1210\/endrev\/bnab037","article-title":"A Modern Approach to Dyslipidemia","volume":"43","author":"Berberich","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"742408","DOI":"10.1155\/2015\/742408","article-title":"Influence of Abdominal Obesity on the Lipid-Lipoprotein Profile in Apoprotein E2\/4 Carriers: The Effect of an Apparent Duality","volume":"2015","author":"Villeneuve","year":"2015","journal-title":"J. Lipids"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.atherosclerosis.2021.04.001","article-title":"Adiposity and the development of dyslipidemia in APOE \u03b52 homozygous subjects: A longitudinal analysis in two population-based cohorts","volume":"325","author":"Heidemann","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sandor, N., Lukacsi, S., Ungai-Salanki, R., Orgovan, N., Szabo, B., Horvath, R., Erdei, A., and Bajtay, Z. (2016). CD11c\/CD18 Dominates Adhesion of Human Monocytes, Macrophages and Dendritic Cells over CD11b\/CD18. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163120"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1093\/cvr\/cvx224","article-title":"CCR2 expression on circulating monocytes is associated with arterial wall inflammation assessed by 18F-FDG PET\/CT in patients at risk for cardiovascular disease","volume":"114","author":"Verweij","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1177\/09612033231203026","article-title":"Antibody binding activity specific to monocyte scavenger receptor CD36 is frequently detectable in the plasma of patients with antiphospholipid syndrome","volume":"32","author":"Kaneshige","year":"2023","journal-title":"Lupus"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11883-020-00870-8","article-title":"CD36 in Atherosclerosis: Pathophysiological Mechanisms and Therapeutic Implications","volume":"22","author":"Tian","year":"2020","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14960","DOI":"10.1096\/fj.202000177R","article-title":"CD163 deficiency increases foam cell formation and plaque progression in atherosclerotic mice","volume":"34","author":"Svendsen","year":"2020","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/BF03402102","article-title":"Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice","volume":"9","author":"Caligiuri","year":"2003","journal-title":"Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1189\/jlb.2MR0316-117RR","article-title":"Molecular mechanisms of regulation of Toll-like receptor signaling","volume":"100","author":"Leifer","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4239\/wjd.v1.i3.76","article-title":"Metabolic effects of obesity: A review","volume":"1","author":"Singla","year":"2010","journal-title":"World J. Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Dahik, V.D., Frisdal, E., and Le Goff, W. (2020). Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155505"},{"key":"ref_36","first-page":"e38","article-title":"Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association","volume":"133","author":"Mozaffarian","year":"2016","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1161\/01.ATV.19.11.2722","article-title":"Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism","volume":"19","author":"Sijbrands","year":"1999","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12944-018-0841-2","article-title":"The role of splenectomy in lipid metabolism and atherosclerosis (AS)","volume":"17","author":"Ai","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jceh.2014.02.005","article-title":"Gaucher disease","volume":"4","author":"Nagral","year":"2014","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_40","first-page":"253","article-title":"Hematologic manifestations and leukemia in Gaucher\u2019s disease","volume":"11","author":"Ranade","year":"2013","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0002-9610(91)90363-I","article-title":"A 27-year experience with splenectomy for Gaucher\u2019s disease","volume":"161","author":"Fleshner","year":"1991","journal-title":"Am. J. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1111\/eci.12351","article-title":"High-fat diet- and angiotensin II-induced aneurysm concurrently elicits splenic hypertrophy","volume":"44","author":"Gopal","year":"2014","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1194\/jlr.P055699","article-title":"Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France","volume":"57","author":"Wintjens","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Spiewak, J., Doykov, I., Papandreou, A., Hallqvist, J., Mills, P., Clayton, P.T., Gissen, P., Mills, K., and Heywood, W.E. (2023). New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210177"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ymgme.2020.01.007","article-title":"Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease","volume":"129","author":"Sidhu","year":"2020","journal-title":"Mol. Genet. Metab."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/3\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:43:43Z","timestamp":1760028223000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/3\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,27]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["genes16030289"],"URL":"https:\/\/doi.org\/10.3390\/genes16030289","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,27]]}}}