Genetic analysis of a congenital split‑hand/split‑foot malformation 4 pedigree

Abstract

In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split-hand/split-foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG-to-CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen-2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X-ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly-ectodermal dysplasia-cleft syndrome and SHFM4.

Spontaneous resolution of nonimmune hydrops fetalis in a fetus with TP63 gene mutation and LZTR1 gene variants

“…The c.728G>A p.(Arg243Gln) variant has been already reported as pathogenic in several EEC3 patients in the literature. 7 , 8 , 9 , 10 Moreover, similar pathogenic variants were reported at the same amino acid position (c.727C>T p.(Arg243Trp); c.728G>T p.(Arg243Leu)). 7 , 11 , 12 , 13 Arg243 is localized in the DNA binding domain of the TP63 protein, a domain where missense mutations are often described in EEC3 syndrome.…”

Tooth defects of EEC and AEC syndrome caused by heterozygous TP63 mutations in three Chinese families and genotype‐phenotype correlation analyses of TP63‐related disorders

“…SHFM is characterized as split‐hand/foot malformation (Yang, Lin, Zhu, Luo, & Lin, ) (Table ). There are 12 different SHFM‐related TP63 mutations (approximately 9.3% of TP63 mutations), including missense and nonsense mutations (Figure ).…”

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family

“…Mutchinick O. M et al reported R97C in the DNA-binding domain of TP63 in Mexican patients with isolated SHFM (Zenteno et al, 2005). Lin G et al reported that c.728G>A (p.Arg243Gln) in the TP63 gene was associated with SHFM (Yang et al, 2018). There is no report that TP63 translocation causes SHFM.…”

“…As a transcription factor of p53 family, TP63 is encoded by TP63 locating on 3q28 and is homologous to TP53 and TP73 and plays an essential role in regulating epithelial, limb, and craniofacial development (Yang et al, 1999). It is described that TP63 acts as one of the most frequently mutant gene which accounts for about 10% of SHFM (Yang et al, 2018). As of now, 148 TP63 mutations have been identified, including 115 missense/nonsense mutations, five mutations in regulatory sequence, five splicing substitutions, 13 small deletions, five small insertions, one small indels, two gross deletions, and two gross insertions.…”