{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:05:36Z","timestamp":1791993936977,"version":"4.4.0"},"reference-count":73,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Fabry disease (FD) is an X\u2010linked genetic disease due to pathogenic variants in\n                    <jats:italic>GLA<\/jats:italic>\n                    . The phenotype varies depending on the\n                    <jats:italic>GLA<\/jats:italic>\n                    variant, alpha\u2010galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non\u2010pathogenic variants or variants of unknown significance (VUS). This, together with the non\u2010specificity of some FD symptoms, challenges physicians attempting to interpret\n                    <jats:italic>GLA<\/jats:italic>\n                    variants. The traditional way to interpreting pathogenicity is based on a combined approach using allele frequencies, genomic databases, global and disease\u2010specific clinical databases, and in silico tools proposed by the American College of Medical Genetics and Genomics. Here, a panel of FD specialists convened to study how expertise may compare with the traditional approach. Several\n                    <jats:italic>GLA<\/jats:italic>\n                    VUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr, p.Asp313Tyr), were re\u2010analyzed through reviews of patients' charts. The same was done for pathogenic\n                    <jats:italic>GLA<\/jats:italic>\n                    variants with some specificities. Our data suggest that input of geneticists and physicians with wide expertise in disease phenotypes, prevalence, inheritance, biomarkers, alleles frequencies, disease\u2010specific databases, and literature greatly contribute to a more accurate interpretation of the pathogenicity of variants, bringing a significant additional value over the traditional approach.\n                  <\/jats:p>","DOI":"10.1111\/cge.14102","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T06:26:45Z","timestamp":1639981605000},"page":"390-402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease"],"prefix":"10.1111","volume":"101","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 AP\u2010HP University Paris Saclay  Garches France"},{"name":"Division of Medical Genetics University of Versailles\u2010Saint\u2010Quentin\u2010en\u2010Yvelines  Montigny le Bretonneux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Levade","sequence":"additional","affiliation":[{"name":"INSERM UMR1037 Cancer Research Center of Toulouse (CRCT) and Paul Sabatier University  Toulouse France"},{"name":"Clinical Biochemistry Laboratory, Reference Center for Inherited Metabolic Diseases, Federative Institute of Biology University Hospital of Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Hachulla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Clinical Immunology Claude Huriez Hospital, University of Lille  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Knebelmann","sequence":"additional","affiliation":[{"name":"Nephrology\u2010Dialysis Department AP\u2010HP, Necker Enfants Malades Hospital, University of Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Lacombe","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University Hospital of Bordeaux  Bordeaux France"},{"name":"INSERM U1211, University of Bordeaux  Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Leguy","family":"Seguin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Clinical Immunology, Fran\u00e7ois Mitterrand Hospital Dijon University Hospital  Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics APHM, Timone Children Hospital  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"No\u00ebl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Strasbourg University Hospital  Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Pierre","family":"Rab\u00e8s","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics University of Versailles\u2010Saint\u2010Quentin\u2010en\u2010Yvelines  Montigny le Bretonneux France"},{"name":"Department of Biochemistry and Molecular Genetics Ambroise Par\u00e9 University Hospital, APHP, Paris\u2010Saclay University  Boulogne\u2010Billancourt France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-5-30"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-138-4-200302180-00014"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01606034"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199102073240607"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/504601"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.072116"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11070951"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-105080"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050292"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.0310"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380030204"},{"key":"e_1_2_11_13_1","unstructured":"The 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