{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:04:06Z","timestamp":1774645446323,"version":"3.50.1"},"reference-count":47,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T00:00:00Z","timestamp":1593129600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2020,5,13]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Pathogenic DNA variants in the GLI-Kruppel family member 3 (<jats:italic>GLI3)<\/jats:italic> gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported <jats:italic>GLI3<\/jats:italic> variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>297 cases were identified with 127 different variants in the <jats:italic>GLI3<\/jats:italic> gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013\u2009and Beta: 2.548, p&lt;0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p&lt;0.001).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>There are two distinct phenotypes within the GLI3-mediated polydactyly population: anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2020-106948","type":"journal-article","created":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T19:57:06Z","timestamp":1593201426000},"page":"362-368","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Variant type and position predict two distinct limb phenotypes in patients with GLI3-mediated polydactyly syndromes"],"prefix":"10.1136","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3857-2325","authenticated-orcid":false,"given":"Martijn","family":"Baas","sequence":"first","affiliation":[{"name":"Plastic, Reconstructive and Hand Surgery, Erasmus MC, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise Bette","family":"Burger","sequence":"additional","affiliation":[{"name":"Plastic, Reconstructive and Hand Surgery, Erasmus MC, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ans MW","family":"van den Ouweland","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven ER","family":"Hovius","sequence":"additional","affiliation":[{"name":"Plastic, Reconstructive and Hand Surgery, Radboud University Nijmegen, Nijmegen, Gelderland, The Netherlands"},{"name":"Hand and Wrist Centre, Xpert Clinic, Eindhoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annelies","family":"de Klein","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christianne A","family":"van Nieuwenhoven","sequence":"additional","affiliation":[{"name":"Plastic, Reconstructive and Hand Surgery, Erasmus MC, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert Jan H","family":"Galjaard","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2020,6,26]]},"reference":[{"key":"2025100511204746000_58.6.362.1","first-page":"5408","article-title":"Gli3 encodes a 190-kilodalton protein with multiple regions of Gli similarity","volume":"10","author":"Ruppert","year":"1990","journal-title":"Mol Cell Biol"},{"key":"2025100511204746000_58.6.362.2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.029181"},{"key":"2025100511204746000_58.6.362.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80678-9"},{"key":"2025100511204746000_58.6.362.4","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2017.00014","article-title":"Sonic hedgehog signaling in limb development","volume":"5","author":"Tickle","year":"2017","journal-title":"Front Cell Dev Biol"},{"key":"2025100511204746000_58.6.362.5","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1002\/ajmg.a.35874","article-title":"A de novo GLI3 mutation in a patient with acrocallosal syndrome","volume":"161A","author":"Speksnijder","year":"2013","journal-title":"Am J Med Genet A"},{"key":"2025100511204746000_58.6.362.6","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.9.1769"},{"key":"2025100511204746000_58.6.362.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-266"},{"key":"2025100511204746000_58.6.362.8","doi-asserted-by":"publisher","DOI":"10.1086\/302557"},{"key":"2025100511204746000_58.6.362.9","article-title":"Gene symbol: Gli3. disease: Pallister-Hall syndrome","volume":"114","author":"Kalff-Suske","year":"2004","journal-title":"Hum Genet"},{"key":"2025100511204746000_58.6.362.10","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21328"},{"key":"2025100511204746000_58.6.362.11","doi-asserted-by":"publisher","DOI":"10.1086\/429346"},{"key":"2025100511204746000_58.6.362.12","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.62"},{"key":"2025100511204746000_58.6.362.13","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12952"},{"key":"2025100511204746000_58.6.362.14","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-269"},{"key":"2025100511204746000_58.6.362.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2009.02.017"},{"key":"2025100511204746000_58.6.362.16","doi-asserted-by":"publisher","DOI":"10.1007\/s13353-012-0109-x"},{"key":"2025100511204746000_58.6.362.17","doi-asserted-by":"publisher","DOI":"10.1093\/pan\/mpq025"},{"key":"2025100511204746000_58.6.362.18","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10212"},{"key":"2025100511204746000_58.6.362.19","unstructured":"Biesecker LG . Pallister-Hall syndrome. Seattle WA: GeneReviews((R)), 1993."},{"key":"2025100511204746000_58.6.362.20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-6442-0_17","article-title":"Describing sequence variants using HGVS nomenclature","volume":"1492","author":"den Dunnen","year":"2017","journal-title":"Methods Mol Biol"},{"key":"2025100511204746000_58.6.362.21","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1002\/ajmg.a.32097","article-title":"Nonsense-Mediated decay and the molecular pathogenesis of mutations in Sall1 and Gli3","volume":"143A","author":"Furniss","year":"2007","journal-title":"Am J Med Genet A"},{"key":"2025100511204746000_58.6.362.22","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00443-06"},{"key":"2025100511204746000_58.6.362.23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.12.8143"},{"key":"2025100511204746000_58.6.362.24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007471"},{"key":"2025100511204746000_58.6.362.25","doi-asserted-by":"publisher","DOI":"10.1080\/10705510701575602"},{"key":"2025100511204746000_58.6.362.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2012.01866.x"},{"key":"2025100511204746000_58.6.362.27","doi-asserted-by":"publisher","DOI":"10.3171\/JNS-07\/09\/0495"},{"key":"2025100511204746000_58.6.362.28","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cca.2011.02.007","article-title":"A novel frame-shift mutation of Gli3 causes non-syndromic and complex digital anomalies in a Chinese family","volume":"412","author":"Cheng","year":"2011","journal-title":"Clin Chim Acta"},{"key":"2025100511204746000_58.6.362.29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/ajmg.a.20018","article-title":"Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified Gli3 mutations","volume":"120A","author":"Debeer","year":"2003","journal-title":"Am J Med Genet A"},{"key":"2025100511204746000_58.6.362.30","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.11.804"},{"key":"2025100511204746000_58.6.362.31","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.066027"},{"key":"2025100511204746000_58.6.362.32","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.13"},{"key":"2025100511204746000_58.6.362.33","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/ajmg.a.33495","article-title":"Metopic craniosynostosis due to mutations in Gli3: a novel association","volume":"152A","author":"McDonald-McGinn","year":"2010","journal-title":"Am J Med Genet A"},{"key":"2025100511204746000_58.6.362.34","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.mgene.2014.11.002","article-title":"A novel GLI3c.750delC truncation mutation in a multiplex Greig cephalopolysyndactyly syndrome family with an unusual phenotypic combination in a patient","volume":"2","author":"Patel","year":"2014","journal-title":"Meta Gene"},{"key":"2025100511204746000_58.6.362.35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/pd.4506","article-title":"Prenatal diagnosis of Greig cephalopolysyndactyly syndrome: a case report","volume":"35","author":"Raposo","year":"2015","journal-title":"Prenat Diagn"},{"key":"2025100511204746000_58.6.362.36","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s00431-013-1938-2","article-title":"Two Indian families with Greig cephalopolysyndactyly with non-syndromic phenotype","volume":"172","author":"Sethi","year":"2013","journal-title":"Eur J Pediatr"},{"key":"2025100511204746000_58.6.362.37","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320160304"},{"key":"2025100511204746000_58.6.362.38","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.cca.2014.03.012","article-title":"Novel frame-shift mutations of Gli3 gene in non-syndromic Postaxial polydactyly patients","volume":"433","author":"Wang","year":"2014","journal-title":"Clin Chim Acta"},{"key":"2025100511204746000_58.6.362.39","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/jhg.2016.76","article-title":"Exome sequencing reveals a novel nonsense mutation of GLI3 in a Chinese family with 'non-syndromic' pre-axial polydactyly","volume":"61","author":"Xiang","year":"2016","journal-title":"J Hum Genet"},{"key":"2025100511204746000_58.6.362.40","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1002\/ajmg.a.38415","article-title":"A novel missense variant in the Gli3 zinc finger domain in a family with digital anomalies","volume":"173","author":"Crapster","year":"2017","journal-title":"Am J Med Genet A"},{"key":"2025100511204746000_58.6.362.41","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1097\/SAP.0000000000001685","article-title":"A novel frameshift mutation of Gli3 causes isolated Postaxial polydactyly","volume":"82","author":"Ni","year":"2019","journal-title":"Ann Plast Surg"},{"key":"2025100511204746000_58.6.362.42","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/cga.12139","article-title":"Gli3 mutations in syndromic and non-syndromic polydactyly in two Indian families","volume":"56","author":"Patel","year":"2016","journal-title":"Congenit Anom"},{"key":"2025100511204746000_58.6.362.43","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1089\/gtmb.2018.0096","article-title":"Mutational screening of Gli3, Shh, and Shh ZRS in 78 Chinese children with nonsyndromic polydactyly","volume":"22","author":"Rao","year":"2018","journal-title":"Genet Test Mol Biomarkers"},{"key":"2025100511204746000_58.6.362.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.07.022"},{"key":"2025100511204746000_58.6.362.45","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/ajmg.a.20318","article-title":"Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome","volume":"123A","author":"Johnston","year":"2003","journal-title":"Am J Med Genet A"},{"key":"2025100511204746000_58.6.362.46","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1093\/hmg\/ddx335","article-title":"Gli1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome","volume":"26","author":"Palencia-Campos","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2025100511204746000_58.6.362.47","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36183"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmedgenet-2020-106948","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T18:20:53Z","timestamp":1759688453000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmedgenet-2020-106948"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,26]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,5,21]]},"published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1136\/jmedgenet-2020-106948"],"URL":"https:\/\/doi.org\/10.1136\/jmedgenet-2020-106948","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,26]]}}}