Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway
Abstract Background Split-hand/foot malformation (SHFM) is a congenital disability characterized by the absence or hypoplasia of the central ray of the hands and/or feet. This study reports a causative variant in the TP63 gene in a Chinese family exhibiting limb anomalies associated with SHFM4. Meth...
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BMC
2025-02-01
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| Online Access: | https://doi.org/10.1186/s12864-025-11297-3 |
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| author | Jianlong Zhuang Yanqing Li Yu’e Chen Hegan Zhang Shufen Liu Manman Hu Chunnuan Chen |
| author_facet | Jianlong Zhuang Yanqing Li Yu’e Chen Hegan Zhang Shufen Liu Manman Hu Chunnuan Chen |
| author_sort | Jianlong Zhuang |
| collection | DOAJ |
| description | Abstract Background Split-hand/foot malformation (SHFM) is a congenital disability characterized by the absence or hypoplasia of the central ray of the hands and/or feet. This study reports a causative variant in the TP63 gene in a Chinese family exhibiting limb anomalies associated with SHFM4. Methods Enrolled in this study was a Chinese family with limb anomalies without any other clinical features. Karyotype analysis and chromosomal microarray analysis (CMA) were conducted to identify chromosomal abnormalities. Whole exome sequencing (WES) was utilized to investigate sequence variants, while RNA sequencing assessed differentially expressed genes, with findings confirmed through quantitative PCR (qPCR). Results Karyotype analysis and CMA revealed no chromosomal abnormalities in the family. Subsequently, WES identified a rare heterozygous variant of NM_003722.5: c.956G > A (p.Arg319His) in the TP63 gene in the proband, which was inherited from her father who also presented with limb deformities. However, both of the sister and grandfather of the proband had the same variant but exhibited normal limb morphology. RNA sequencing results demonstrated an increased expression level of TP63 and its downstream genes (PERP, CDH3, and DLX5) compared with the controls, indicating an enrichment of cell adhesion molecules the differentially expressed genes in the patient. However, significant differences were noted only for the CDH3 and DLX5 genes in qPCR analysis (p<0.05). Conclusion This study identifies, for the first time, the TP63 gene variant c.956G > A (p.Arg319His) as a causative factor for SHFM4 in Chinese individuals with incomplete penetrance. In addition, we hypothesize that the p.Arg319His variant functions as a gain-of-function variant, leading to the upregulation of cell adhesion target genes. Such upregulation then disrupts the p63-Dlx signaling pathway and causes AER stratification failure. |
| format | Article |
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| institution | Kabale University |
| issn | 1471-2164 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | BMC Genomics |
| spelling | doaj-art-ce88d4607fc34e9b9fb8ef984db0cebf2025-02-09T12:13:56ZengBMCBMC Genomics1471-21642025-02-0126111010.1186/s12864-025-11297-3Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathwayJianlong Zhuang0Yanqing Li1Yu’e Chen2Hegan Zhang3Shufen Liu4Manman Hu5Chunnuan Chen6Prenatal Diagnosis Center, Quanzhou Women’s and Children’s HospitalPrenatal Diagnosis Center, Quanzhou Women’s and Children’s HospitalDepartment of Ultrasound, Quanzhou Women’s and Children’s HospitalDepartment of Gynecology, Quanzhou Women’s and Children’s HospitalDepartment of Neurology, Rare Disease Medical Center, The Second Affiliated Hospital of Fujian Medical UniversityBerry Genomics CorporationDepartment of Neurology, Rare Disease Medical Center, The Second Affiliated Hospital of Fujian Medical UniversityAbstract Background Split-hand/foot malformation (SHFM) is a congenital disability characterized by the absence or hypoplasia of the central ray of the hands and/or feet. This study reports a causative variant in the TP63 gene in a Chinese family exhibiting limb anomalies associated with SHFM4. Methods Enrolled in this study was a Chinese family with limb anomalies without any other clinical features. Karyotype analysis and chromosomal microarray analysis (CMA) were conducted to identify chromosomal abnormalities. Whole exome sequencing (WES) was utilized to investigate sequence variants, while RNA sequencing assessed differentially expressed genes, with findings confirmed through quantitative PCR (qPCR). Results Karyotype analysis and CMA revealed no chromosomal abnormalities in the family. Subsequently, WES identified a rare heterozygous variant of NM_003722.5: c.956G > A (p.Arg319His) in the TP63 gene in the proband, which was inherited from her father who also presented with limb deformities. However, both of the sister and grandfather of the proband had the same variant but exhibited normal limb morphology. RNA sequencing results demonstrated an increased expression level of TP63 and its downstream genes (PERP, CDH3, and DLX5) compared with the controls, indicating an enrichment of cell adhesion molecules the differentially expressed genes in the patient. However, significant differences were noted only for the CDH3 and DLX5 genes in qPCR analysis (p<0.05). Conclusion This study identifies, for the first time, the TP63 gene variant c.956G > A (p.Arg319His) as a causative factor for SHFM4 in Chinese individuals with incomplete penetrance. In addition, we hypothesize that the p.Arg319His variant functions as a gain-of-function variant, leading to the upregulation of cell adhesion target genes. Such upregulation then disrupts the p63-Dlx signaling pathway and causes AER stratification failure.https://doi.org/10.1186/s12864-025-11297-3Split-hand/foot malformationWhole exome sequencingRNA sequencingTP63Pathogenesis |
| spellingShingle | Jianlong Zhuang Yanqing Li Yu’e Chen Hegan Zhang Shufen Liu Manman Hu Chunnuan Chen Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway BMC Genomics Split-hand/foot malformation Whole exome sequencing RNA sequencing TP63 Pathogenesis |
| title | Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway |
| title_full | Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway |
| title_fullStr | Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway |
| title_full_unstemmed | Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway |
| title_short | Molecular characterization of a rare TP63 variant associated with split-hand/split-foot malformation 4 and incomplete penetrance: disruption of the p63-Dlx signaling pathway |
| title_sort | molecular characterization of a rare tp63 variant associated with split hand split foot malformation 4 and incomplete penetrance disruption of the p63 dlx signaling pathway |
| topic | Split-hand/foot malformation Whole exome sequencing RNA sequencing TP63 Pathogenesis |
| url | https://doi.org/10.1186/s12864-025-11297-3 |
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