{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:19:03Z","timestamp":1784200743252,"version":"3.55.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018916","name":"Suzhou Municipal Health Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018916","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      GLI family zinc finger 3 (\n                      <jats:italic>GLI3<\/jats:italic>\n                      ) is a transcription factor involved in limb development.\n                      <jats:italic>GLI3<\/jats:italic>\n                      gene variants have been shown to be associated with several human congenital limb malformations, including Greig cephalopolysyndactyly, Pallister\u2013Hall syndrome, non-syndromic postaxial polydactyly (PAP-A\/B), and preaxial polydactyly type IV (PPD-IV). The aim of this study was to identify\n                      <jats:italic>GLI3<\/jats:italic>\n                      gene variants in ten Chinese families with limb malformations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Ten Chinese families with limb malformations were recruited. Variant screening in probands was then performed using NGS, with candidate pathogenic variants verified by polymerase chain reaction (PCR) combined with Sanger DNA sequencing. Variant pathogenicity was evaluated using bioinformatics, evolutionary conservation, and disease and mutant allele co-segregation approaches. The biological effects of missense variants were predicted by three-dimensional protein conformation analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ten\n                      <jats:italic>GLI3<\/jats:italic>\n                      variants were identified: two missense variants c.1063G&amp;gt;A (p.Val355Ile) and c.1489C&amp;gt;A (p.Leu497Ile), four nonsense variants c.2374C&amp;gt;T (p.Arg792*), c.2008C&amp;gt;T (p.Gln670*), c.1096\u00a0C&amp;gt;T (p.Arg366*), and c.2029C&amp;gt;T (p.Gln677*); three frameshift variants c.600delC (p.Tyr200*), c.1880_1881del (p.His627Argfs*48), and c.811_812delCT (p.Leu271Serfs*5); a large fragment deletion of NC_000007.14: g.42061081_42069739. Seven of these ten variants have never been recorded in the Human Gene Variant Database.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Ten\n                      <jats:italic>GLI3<\/jats:italic>\n                      variants were successfully identified in families with different limb malformations, indicating significant clinical and allelic heterogeneity of\n                      <jats:italic>GLI3<\/jats:italic>\n                      -related limb malformations. The present study expands the spectra of pathogenic variants and clinical manifestation for\n                      <jats:italic>GLI3<\/jats:italic>\n                      -related morphological disorder and provides solid evidence for genetic counseling and prenatal gene diagnosis in the affected families.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2025.1650790","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T04:57:57Z","timestamp":1759985877000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The molecular characterization of seven novel GLI family zinc finger 3 (GLI3) variants in Chinese families with limb malformations"],"prefix":"10.3389","volume":"16","author":[{"given":"Siyuan","family":"Tao","sequence":"first","affiliation":[{"name":"Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]},{"name":"Center for Rare Diseases, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]},{"name":"Department of Medical Genetics, State Key Laboratory for Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyu","family":"Gu","sequence":"additional","affiliation":[{"name":"Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]},{"name":"Center for Rare Diseases, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]},{"name":"Department of Medical Genetics, State Key Laboratory for Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"B1","first-page":"457","article-title":"GLI3-related polydactyly: a review","volume-title":"Clin. 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