{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:54:03Z","timestamp":1790376843722,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2703900"],"award-info":[{"award-number":["2022YFC2703900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81000783"],"award-info":[{"award-number":["81000783"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Heterozygous <jats:italic>TP63<\/jats:italic> mutations cause a spectrum of disorders including split\u2010hand\/foot malformation 4 (SHFM4) and ectrodactyly\u2010ectodermal dysplasia\u2010cleft lip\/palate syndrome 3 (EEC3). While some SHFM4 mutations concurrently induce EEC3\u2010like phenotypes (designated SHFM4\/EEC3 mutations), their prevalence and distribution\u2014particularly those near the p63 C\u2010terminus\u2014remain poorly characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>A multigenerational Chinese family with an isolated form of SHFM was investigated. Genetic analysis included real\u2010time quantitative PCR and Sanger sequencing. Disease mutation databases and literature were systematically reviewed to identify all reported <jats:italic>TP63<\/jats:italic> mutations causing isolated SHFM4 and to classify these mutations by clinical phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a novel likely pathogenic variant (NM_003722.5: c.2032G&gt;C, p.E678Q) within a sumoylation motif near the C\u2010terminus of p63. Analysis of 72 families (182 carriers) revealed 28 SHFM4\u2010causing <jats:italic>TP63<\/jats:italic> mutations, comprising 12 dual\u2010phenotype SHFM4\/EEC3 mutations and 16 isolated SHFM4\u2010only mutations. Certain clinical traits of SHFM4 mutations and distribution characteristics for SHFM4\u2010only mutations were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study expands the SHFM4 mutation spectrum, demonstrating significant overlap between SHFM4 mutations and EEC3 mutations. The p.E678Q represents the most reliable SHFM4\u2010only mutation near the protein C\u2010terminus. These findings will improve molecular classification and genetic counseling for <jats:italic>TP63<\/jats:italic>\u2010related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70140","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T09:40:56Z","timestamp":1758188456000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel <scp><i>TP63<\/i><\/scp> Missense Mutation in the Sumoylation Motif Causes Isolated Split\u2010Hand\/Foot Malformation 4: A Pedigree Report and Literature Review"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0041-468X","authenticated-orcid":false,"given":"Wei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Capital Institute of Pediatrics  Beijing China"},{"name":"McKusick\u2010Zhang Center for Genetic Medicine, 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  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[{"name":"McKusick\u2010Zhang Center for Genetic Medicine, 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  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1985-3420","authenticated-orcid":false,"given":"Nuo","family":"Si","sequence":"additional","affiliation":[{"name":"McKusick\u2010Zhang Center for Genetic Medicine, 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  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"McKusick\u2010Zhang Center for Genetic Medicine, 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  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15319"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.1.55"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1170005"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.4.1.1359"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.3.12.1290"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61762"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0174122"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1039"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.011759"},{"key":"e_1_2_12_13_1","unstructured":"Online Mendelian Inheritance in Man.2022.\u201cOMIM.\u201dJohns Hopkins University Baltimore MD. 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