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The variants in the <jats:italic>GLI3<\/jats:italic> gene are closely related to congenital limb malformations. However, the causes underlying polydactyly and syndactyly are not well understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a whole\u2010exome sequencing on two four\u2010generation Chinese families with polydactyly and syndactyly. Then c.2374C&gt;T and c.1728C&gt;A mutant plasmids were transfected to HEK293T cells and mice limb bud cells to explore the functional consequences of these variants. Western blot and real\u2010time quantitative PCR were used to analyze the expression of GLI3 and Shh.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In these two families, the known <jats:italic>GLI3<\/jats:italic> variant (NM_000168.6:c.2374C&gt;T) and the novel <jats:italic>GLI3<\/jats:italic> variant (NM_000168.6:c.1728C&gt;A) contributed to polydactyly and syndactyly. Additionally, the <jats:italic>GLI3<\/jats:italic> c.2374C&gt;T mutant plasmid led to truncated GLI3 protein, and the <jats:italic>GLI3<\/jats:italic> c.1728C&gt;A mutant plasmid led to degraded GLI3 protein. Simultaneously, we demonstrated that the <jats:italic>GLI3<\/jats:italic>\u2010mutant plasmids led to decreased Shh expression in mice limb bud cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We demonstrated that the novel <jats:italic>GLI3<\/jats:italic> variant (c.1728C&gt;A) and known <jats:italic>GLI3<\/jats:italic> variant (c.2374C&gt;T) contributed to the malformations in two four\u2010generation pedigrees with polydactyly and syndactyly by affecting SHH signaling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1895","type":"journal-article","created":{"date-parts":[[2022,2,26]],"date-time":"2022-02-26T09:14:00Z","timestamp":1645866840000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Two nonsense <scp>GLI3<\/scp> variants are associated with polydactyly and syndactyly in two families by affecting the sonic hedgehog signaling pathway"],"prefix":"10.1002","volume":"10","author":[{"given":"Xiaofang","family":"Shen","sequence":"first","affiliation":[{"name":"Soochow University  Suzhou China"},{"name":"Department of Orthopedics Children's Hospital of Soochow University  Suzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics First Affiliated Hospital, Sun Yat\u2010sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Research Unit, Tongji Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taifeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics First Affiliated Hospital, Sun Yat\u2010sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1742-0186","authenticated-orcid":false,"given":"Yongjun","family":"Rui","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Wuxi Ninth People's Hospital Affiliated to Soochow University  Wuxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,2,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/gtmb.2019.0071"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12952"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2012.03.012"},{"issue":"10","key":"e_1_2_11_5_1","first-page":"1","article-title":"The Greig cephalopolysyndactyly syndrome","volume":"3","author":"Biesecker L. 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