A Novel TP63 Missense Mutation in the Sumoylation Motif Causes Isolated Split-Hand/Foot Malformation 4: A Pedigree Report and Literature Review.

backgroundHeterozygous TP63 mutations cause a spectrum of disorders including split-hand/foot malformation 4 (SHFM4) and ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3). While some SHFM4 mutations concurrently induce EEC3-like phenotypes (designated SHFM4/EEC3 mutations), their prevalence and distribution-particularly those near the p63 C-terminus-remain poorly characterized.

methodA multigenerational Chinese family with an isolated form of SHFM was investigated. Genetic analysis included real-time quantitative PCR and Sanger sequencing. Disease mutation databases and literature were systematically reviewed to identify all reported TP63 mutations causing isolated SHFM4 and to classify these mutations by clinical phenotypes.

resultsWe identified a novel likely pathogenic variant (NM_003722.5: c.2032G>C, p.E678Q) within a sumoylation motif near the C-terminus of p63. Analysis of 72 families (182 carriers) revealed 28 SHFM4-causing TP63 mutations, comprising 12 dual-phenotype SHFM4/EEC3 mutations and 16 isolated SHFM4-only mutations. Certain clinical traits of SHFM4 mutations and distribution characteristics for SHFM4-only mutations were observed.

conclusionsThis study expands the SHFM4 mutation spectrum, demonstrating significant overlap between SHFM4 mutations and EEC3 mutations. The p.E678Q represents the most reliable SHFM4-only mutation near the protein C-terminus. These findings will improve molecular classification and genetic counseling for TP63-related disorders.