{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:02:56Z","timestamp":1776934976627,"version":"3.51.2"},"reference-count":39,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T00:00:00Z","timestamp":1583884800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2020,1,3]]},"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Fabry disease (\u03b1-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic <jats:italic>GLA<\/jats:italic> variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified <jats:italic>GLA<\/jats:italic> variants from the <jats:italic>GLA<\/jats:italic>-specific fabry-database.org database.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A Fabry disease genotype\u2013phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan\u2013Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Final consensus on classifications of \u2018pathogenic\u2019 was achieved for 32 of 33 <jats:italic>GLA<\/jats:italic> variants (26 \u2018classic\u2019 phenotype, 171 males; 6 \u2018later-onset\u2019 phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between \u2018classic\u2019 and \u2018later-onset\u2019 phenotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The iterative system implemented by a Fabry disease genotype\u2013phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular <jats:italic>GLA<\/jats:italic> variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2019-106467","type":"journal-article","created":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T17:15:41Z","timestamp":1583946941000},"page":"542-551","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":62,"title":["Use of a rare disease registry for establishing phenotypic classification of previously unassigned <i>GLA<\/i> variants: a consensus classification system by a multispecialty Fabry disease genotype\u2013phenotype workgroup"],"prefix":"10.1136","volume":"57","clinical-trial-number":[{"clinical-trial-number":"nct00196742","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8355-007X","authenticated-orcid":false,"given":"Dominique P","family":"Germain","sequence":"first","affiliation":[{"name":"French Referral Centre for Fabry disease, Division of Medical Genetics, University of Versailles, Paris-Saclay University, Montigny, France"}]},{"given":"Jo\u00e3o Paulo","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Genetics, S\u00e3o Jo\u00e3o Hospital Centre & Faculty of Medicine, University of Porto, Porto, Portugal"},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal"}]},{"given":"Daniel G","family":"Bichet","sequence":"additional","affiliation":[{"name":"Nephrology Service, Research Center, H\u00f4pital du Sacr\u00e9-Coeur de Montr\u00e9al, Montreal, Qu\u00e9bec, Canada"},{"name":"Departments of Medicine, Pharmacology and Physiology, University of Montreal, Montreal, Qu\u00e9bec, Canada"}]},{"given":"Han-Wook","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Asan Medical Center Children\u2019s Hospital, University of Ulsan College of Medicine, Seoul, South Korea"}]},{"given":"Robert J","family":"Hopkin","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA"}]},{"given":"Roberta","family":"Lemay","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme, Cambridge, Massachusetts, USA"}]},{"given":"Juan","family":"Politei","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fundaci\u00f3n Para el Estudio de Enfermedades Neur\u00f3metabolicas (FESEN), Buenos Aires, Argentina"}]},{"given":"Christoph","family":"Wanner","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University Clinic, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}]},{"given":"William R","family":"Wilcox","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA"}]},{"given":"David G","family":"Warnock","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA"}]}],"member":"239","published-online":{"date-parts":[[2020,3,11]]},"reference":[{"key":"2025100521381852000_57.8.542.1","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-5-30","article-title":"Fabry disease","volume":"5","author":"Germain","year":"2010","journal-title":"Orphanet J Rare Dis"},{"key":"2025100521381852000_57.8.542.2","doi-asserted-by":"publisher","DOI":"10.1007\/s100380170088"},{"key":"2025100521381852000_57.8.542.3","first-page":"227","article-title":"Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype\/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes","volume":"48","author":"Ashton-Prolla","year":"2000","journal-title":"J Investig Med"},{"key":"2025100521381852000_57.8.542.4","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000472202","article-title":"Fabry disease: fourteen \u03b1-galactosidase A mutations in unrelated families from the United Kingdom and other European countries","volume":"4","author":"Davies","year":"1996","journal-title":"Eur J Hum Genet"},{"key":"2025100521381852000_57.8.542.5","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/BF03401671","article-title":"Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes","volume":"3","author":"Eng","year":"1997","journal-title":"Mol Med"},{"key":"2025100521381852000_57.8.542.6","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.10.1795"},{"key":"2025100521381852000_57.8.542.7","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s004390050292","article-title":"Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease","volume":"98","author":"Germain","year":"1996","journal-title":"Hum Genet"},{"key":"2025100521381852000_57.8.542.8","doi-asserted-by":"publisher","DOI":"10.1159\/000060194"},{"key":"2025100521381852000_57.8.542.9","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.0310"},{"key":"2025100521381852000_57.8.542.10","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/BF03402156","article-title":"Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes","volume":"8","author":"Germain","year":"2002","journal-title":"Mol Med"},{"key":"2025100521381852000_57.8.542.11","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.2659"},{"key":"2025100521381852000_57.8.542.12","doi-asserted-by":"publisher","DOI":"10.1086\/339431"},{"key":"2025100521381852000_57.8.542.13","doi-asserted-by":"publisher","DOI":"10.1007\/BF00207037"},{"key":"2025100521381852000_57.8.542.14","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.3.503"},{"key":"2025100521381852000_57.8.542.15","first-page":"784","article-title":"Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease","volume":"47","author":"Sakuraba","year":"1990","journal-title":"Am J Hum Genet"},{"key":"2025100521381852000_57.8.542.16","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(02)00012-4"},{"key":"2025100521381852000_57.8.542.17","doi-asserted-by":"publisher","DOI":"10.1186\/1479-7364-2-5-297"},{"key":"2025100521381852000_57.8.542.18","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1007\/BF03401993","article-title":"Twenty novel mutations in the \u03b1-galactosidase A gene causing Fabry disease","volume":"5","author":"Topaloglu","year":"1999","journal-title":"Mol Med"},{"key":"2025100521381852000_57.8.542.19","doi-asserted-by":"crossref","first-page":"504784","DOI":"10.1155\/2015\/504784","article-title":"High variability of Fabry disease manifestations in an extended Italian family","volume":"2015","author":"Cammarata","year":"2015","journal-title":"Biomed Res Int"},{"key":"2025100521381852000_57.8.542.20","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/cge.12261","article-title":"Intrafamilial phenotypic variability in four families with Anderson-Fabry disease","volume":"86","author":"Rigoldi","year":"2014","journal-title":"Clin Genet"},{"key":"2025100521381852000_57.8.542.21","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016090964"},{"key":"2025100521381852000_57.8.542.22","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.ymgme.2018.02.014","article-title":"Fabry disease revisited: management and treatment recommendations for adult patients","volume":"123","author":"Ortiz","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2025100521381852000_57.8.542.23","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025100521381852000_57.8.542.24","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12613"},{"key":"2025100521381852000_57.8.542.25","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2011.31"},{"key":"2025100521381852000_57.8.542.26","first-page":"7.13.1","article-title":"Sequence variant descriptions: HGVS nomenclature and Mutalyzer","volume":"90","author":"den Dunnen","year":"2016","journal-title":"Curr Protoc Hum Genet"},{"key":"2025100521381852000_57.8.542.27","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2010.58"},{"key":"2025100521381852000_57.8.542.28","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCGENETICS.116.001639","article-title":"Fabry disease in families with hypertrophic cardiomyopathy: clinical manifestations in the classic and later-onset phenotypes","volume":"10","author":"Adalsteinsdottir","year":"2017","journal-title":"Circ Cardiovasc Genet"},{"key":"2025100521381852000_57.8.542.29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.50.070181.002025"},{"key":"2025100521381852000_57.8.542.30","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/gim.2016.122","article-title":"The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat","volume":"19","author":"Benjamin","year":"2017","journal-title":"Genet Med"},{"key":"2025100521381852000_57.8.542.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(07)80122-6"},{"key":"2025100521381852000_57.8.542.32","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ymgme.2018.06.004","article-title":"European expert consensus statement on therapeutic goals in Fabry disease","volume":"124","author":"Wanner","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2025100521381852000_57.8.542.33","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-016-0441-z","article-title":"Alpha-galactosidase A p.A143T, a non-Fabry disease-causing variant","volume":"11","author":"Lenders","year":"2016","journal-title":"Orphanet J Rare Dis"},{"key":"2025100521381852000_57.8.542.34","first-page":"101","article-title":"Questioning the Pathogenic Role of the GLA p.Ala143Thr \"Mutation\" in Fabry Disease: Implications for Screening Studies and ERT","volume":"8","author":"Terryn","year":"2013","journal-title":"JIMD Rep"},{"key":"2025100521381852000_57.8.542.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2012.11.003"},{"key":"2025100521381852000_57.8.542.36","first-page":"1","article-title":"The renal history of Fabry disease","volume":"33","author":"Gaggl","year":"2016","journal-title":"G Ital Nefrol"},{"key":"2025100521381852000_57.8.542.37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/cge.12449","article-title":"Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance","volume":"88","author":"Smid","year":"2015","journal-title":"Clin Genet"},{"key":"2025100521381852000_57.8.542.38","doi-asserted-by":"crossref","unstructured":"Germain DP , Jurca-Simina IE . Principles of human genetics and Mendelian inheritance. In: Burlina AP , ed. Neurometabolic hereditary diseases of adults. Cham, Switzerland: Springer, 2018: 1\u201328.doi:10.1007\/978-3-319-76148-0","DOI":"10.1007\/978-3-319-76148-0_1"},{"key":"2025100521381852000_57.8.542.39","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1003632","article-title":"Functional characterisation of alpha-galactosidase A mutations as a basis for a new classification system in Fabry disease","volume":"9","author":"Lukas","year":"2013","journal-title":"PLoS Genet"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmedgenet-2019-106467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T04:38:33Z","timestamp":1759725513000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmedgenet-2019-106467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,11]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,7,23]]},"published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1136\/jmedgenet-2019-106467"],"URL":"https:\/\/doi.org\/10.1136\/jmedgenet-2019-106467","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,11]]}}}