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It exhibits significant etiological and clinical diversity. This study aims to identify the pathogenic cause in two patients with sub\u2010PHS (sub\u2010Pallister\u2013Hall Syndrome) and PAP (postaxial polydactyly), respectively, from two Chinese pedigrees.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Exome sequencing was performed on patients to screen for potential pathogenic variants. Subsequently, these variants were validated by Sanger sequencing. The c.3342dupC and c.4431dupT mutant plasmids were transfected into HEK293T cells, and the effects of <jats:italic>GLI3<\/jats:italic> mutations on transcription and protein levels were analyzed via qRT\u2010PCR and Western blot. Additionally, Swiss Model was utilized to predict the effects of mutations on protein tertiary structure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mutations of <jats:italic>GLI3<\/jats:italic> (NM_000168.6: c.3342dupC; p. A1115Rfs*14) (NM_000168.6: c.4431dupT; p. Glu1478Ter) were identified in affected individuals. These mutations were present exclusively in the patients and absent in the healthy individuals. No significant difference in transcription levels between the mutations and wild type was observed. Functional analysis revealed that the truncated variants p. A1115Rfs*14 and p. Glu1478Ter exhibited reduced molecular weight and potential functional impairment due to protein retention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The mutations p. A1115Rfs*14 and p. Glu1478Ter in <jats:italic>GLI3<\/jats:italic> may account for sub\u2010PHS and PAP in the two patients, respectively. This finding expands the mutation and phenotype spectrum associated with <jats:italic>GLI3<\/jats:italic>, providing valuable insights for the clinical diagnosis of polysyndactyly.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70088","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T15:44:16Z","timestamp":1741707856000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Two Nonsense <i>GLI3<\/i> Variants Are Identified in Two Chinese Families With Polydactyly"],"prefix":"10.1002","volume":"13","author":[{"given":"Yongzhen","family":"Qi","sequence":"first","affiliation":[{"name":"School of Medical Laboratory, Shandong Second Medical University  Weifang Shandong China"},{"name":"Linyi Peoples' Hospital, Shandong Second Medical University  Linyi Shandong China"},{"name":"Department of Laboratory Medicine Linyi Peoples' Hospital  Linyi Shandong China"},{"name":"Key Laboratory for 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