{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:52:18Z","timestamp":1792479138554,"version":"4.5.0"},"reference-count":26,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:00:00Z","timestamp":1760832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:00:00Z","timestamp":1760832000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Fabry disease (FD) is a lysosomal storage disease due to genetic variants in the\n                    <jats:italic>GLA<\/jats:italic>\n                    gene located on the X chromosome. Males are hemizygous, while many females are genetic mosaics due to the random inactivation of the X chromosome. While most of the identified variants are deleterious for\n                    <jats:italic>GLA<\/jats:italic>\n                    , in some cases, less rare gene variants have been considered responsible for some FD features.\n                    <jats:italic>GLA<\/jats:italic>\n                    variants were selected from the database of 469 thousand genotyped subjects of the UK Biobank database. Pathogenic variants (ALL_P), variants of uncertain significance (ALL_U), and variants with conflicting interpretations of pathogenicity (ALL_C) were grouped, while p.Asp313Tyr, p.Ala143Thr, p.Ser126Gly, p.Arg118Cys, and p.Asn215Ser were evaluated individually. More than 480 thousand subjects not carrying variants in the\n                    <jats:italic>GLA<\/jats:italic>\n                    gene were used as controls in association studies. Clinical and biochemical phenotypes were extracted from the same database, and a FD phenotype score (FASTEX derived Fabry, FDF score) was derived from the FASTEX prognostic to assess the probability of an FD phenotype score. Pathogenic variants and p.Asn215Ser were associated with FDF score, while all other variants were not associated with any FDF feature. Stratification of patients based on a calculated cardiovascular (CV) risk score demonstrated that patients with nonpathogenic variants within the highest CV risk quartile (&gt;\u200975th percentile) showed characteristic features of FD, whereas those in the lower risk group (&lt;\u200975th percentile) showed odds ratios indicating inverse association with FD features. In conclusion, the data from UK Biobank suggest that pathogenic variants are always associated with FD features, while variants of uncertain significance and conflicting interpretation acquire an FD phenotype only in the presence of a high CV risk burden.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70103","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T02:00:16Z","timestamp":1760925616000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Clinical and Biochemical Characterization of Fabry Disease Associated\n                    <scp>\n                      <i>GLA<\/i>\n                    <\/scp>\n                    Gene Variants: Data From a Large Cohort of 469 Thousand Genotyped Subjects of the\n                    <scp>UK<\/scp>\n                    Biobank Database"],"prefix":"10.1002","volume":"48","author":[{"given":"Antonina","family":"Giammanco","sequence":"first","affiliation":[{"name":"Regional Center for the Prevention Diagnosis and Cure of the Rare Metabolic Diseases (CERMMET)  Sicily Italy"},{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola Maria","family":"Gagliardo","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Scrimali","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Brucato","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa Maria Grazia","family":"Fasciana","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Averna","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"},{"name":"Institute of Biophysics (IBF), National Research Council (CNR)  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo Baldassare","family":"Cefalu","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Noto","sequence":"additional","affiliation":[{"name":"Regional Center for the Prevention Diagnosis and Cure of the Rare Metabolic Diseases (CERMMET)  Sicily Italy"},{"name":"Department of Health Promotion, Maternal and Child Health, Internal and Specialized Medicine of Excellence \u201cG. D. Alessandro\u201d (PROMISE) University of Palermo  Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,19]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"1993","volume-title":"GeneReviews [Internet]","author":"Mehta A.","year":"2002"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14102"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010024\u201003500\u20107"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.6515\/ACS.202409_40(5).20240731A"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gimo.2024.101891"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae148"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfw082"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00438\u2010024\u201002202\u2010w"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201032464\u20100"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27196"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen\u20102017\u2010017098"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13007"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12240"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2012_167"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00336"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2012.11.003"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl\u20102019\u2010315933"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12743"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1912"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2023.101029"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2023.107700"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2018_146"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.016083"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.11.004"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.389"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.70103","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.70103","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.70103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:12:11Z","timestamp":1784679131000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.70103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,19]]},"references-count":26,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/jimd.70103"],"URL":"https:\/\/doi.org\/10.1002\/jimd.70103","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,19]]},"assertion":[{"value":"2025-01-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70103"}}