Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare autosomal dominant inherited disease caused due to mutations in the TP63 gene. More commonly, mutations in the TP63 gene result in ectodermal dysplasia and/or orofacial cleft. ADULT syndrome is a type of ectoderm-related tissue dysplasia. This case report describes a patient with chronic tearing, congenital atresia, and obstruction of the lacrimal ducts, which are the main clinical manifestations of ADULT syndrome. This patient also presented with some clinical manifestations that were different from those of ADULT syndrome, namely, mild eyelid fusion and abnormal development of the fifth finger (a stiff fifth finger with camptodactyly that was shortened in length). The gene mutation in this patient was also at a site different from those usually reported in the literature. In this patient, c.518G > T resulted in p. G173V (accession number: NM_003722; exon4). We performed successful dacryocystorhinostomy and artificial lacrimal duct implantation. As shown above, we discussed the clinical characteristics and genetics of the disease in detail. In sharing this case, we aim to contribute to the current understanding of the genes and clinical manifestations of ADULT syndrome and to assist clinicians in the clinical diagnosis of TP63 mutation-related diseases.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical AEC case of a four-year-old girl with extensive skin erosions and erythroderma of the scalp and the trunk, and to a lesser extent of the limbs, nail dystrophy on the fingers and toes, xerophthalmia, a high-arched palate, oligodontia, and hypohidrosis. Mutation analysis of the TP63 gene detected a de novo missense mutation in exon 14 (c.1799G>T; p.Gly600Val). We discuss the phenotype-genotype correlation by presenting the clinical features of AEC in the patient, and the effect of the detected mutation in p63 structure and function using protein structural modeling, in view of similar cases in the literature. We performed a molecular modeling study in order to link the effect on the protein structure level of the missense mutation G600V. We noted that the introduction of the bulkier Valine residue in place of the slim Glycine residue caused a significantly altered 3D conformational arrangement of that protein region, pushing away the adjacent antiparallel α helix. We propose that the introduced locally altered structure of the G600V mutant p63 has a significant functional effect on specific protein-protein interactions, thus affecting the clinical phenotype.

In cases of fetal hydrops, searching for an etiology is essential to evaluate the fetal prognosis and propose the most appropriate management.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare genetic disease with an autosomal dominant transmission, characterized by several congenital anomalies. Clinical features include ectodermal defects affecting the skin, hair, teeth, nails and sweat glands, associated with typical eyelid fusion in addition to a cleft lip and/or palate. The diagnosis is based on clinical criteria and molecular genetic testing of TP63 gene, the gene related to AEC syndrome. In this context, most reported mutations induce an amino acid change in the sterile alpha motif (SAM) domain, and are predicted to disrupt protein-protein interactions. We here describe the case of a 2-year-old Moroccan girl diagnosed with AEC syndrome on the basis of clinical features. The molecular studies and bioinformatics tools revealed a novel heterozygous missense mutation c.1798G>C (p.Gly600Arg) in exon 14 of the TP63 gene, that was not found in her parents. The molecular analysis and the early diagnosis of this syndrome are important to offer appropriate genetic counseling and management to patients and their families.

Undifferentiated carcinoma of the pancreas (UC) is a carcinoma without a definitive direction of differentiation. Tumour protein p63 is a regulator of squamous phenotype, which may also be engaged in tumour development. N-terminal isoforms of p63 are TAp63 and ΔNp63. Pan-p63 antibodies are able to detect both isoforms, whereas p40 antibodies recognise the ΔNp63 isoform only. The aim of the study was to describe pan-p63/p40 immunohistochemical expression patterns in pancreatic neoplasms: UC, ductal adenocarcinomas, neuroendocrine tumours, neuroendocrine carcinomas, serous cystic neoplasms, and solid pseudopapillary neoplasms. DAK-p63 and BC28 antibodies were used for pan-p63 and p40 detection, respectively. Moderate-to-strong pan-p63 was found in anaplastic (pleomorphic giant cell) UC (n = 4), sarcomatoid UC (n = 2), UC with osteoclast-like giant cells (n = 3), and ductal carcinomas with partial squamous differentiation. Weak and focal pan-p63 expression was found in monomorphic UC (n = 3) and in the majority of neuroendocrine carcinomas (6/7 cases). Pan-p63 expression was infrequent in ductal carcinomas without squamous differentiation and in neuroendocrine tumours. Serous cystic and solid pseudopapillary neoplasms were pan-p63-negative. Ductal carcinomas with partial squamous differentiation were the only tumours with evident p40 expression. Pan-p63(+)/p40(-) immunohistochemical status may be supportive for UC diagnosis. The pan-p63 expression was not equivalent to squamous differentiation in pancreatic neoplasia.

The tumor protein p63encoded by the gene TP63 acts as a homologue of p53 protein. TP63 gene is the transformation factor with two initiation sites for transcriptional process and is related with stress, signal transduction and cell cycle control. The biasness in the preference of a few codons more frequently over other synonymous codons is the codon usage bias (CUB). Natural selection and mutational pressure are the two prime evolutionary forces acting on CUB. Here, the bioinformatic based analysis was performed to investigate the base distribution and CUB of TP63transcript variants (isoforms) as no work was performed earlier. Analysis of compositional features revealed variation in base content across TP63 gene isoforms and the GC content was more than 50%, indicating GC richness of its isoforms. The mean effective number of codons (ENC), a measure of CUB, was 51.83, i.e. overall CUB of TP63 gene was low. Among 13 isoforms of TP63 gene, nature selected against the CTA codon in 8 isoforms and favored five over-represented (RSCU > 1.6) codons namely CTG, CAG, ATC, AAC and GCC during evolution. Correlation between overall nucleotide composition and its 3rd codon position revealed that both mutational pressure and natural selection moulded its CUB. Further, the correlation between ENC and aromaticity depicted that variation of CUB was related to the degree of aromaticity of p63 protein.

Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive.
The purpose of this study was to identify the underlying genetic cause in probands with ACM.
DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes-DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes.
About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency.
Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.

OBJECTIVE: Genome-wide association studies (GWAS) have led to the identification of a bladder cancer susceptibility variant (rs710521) in a non-coding intergenic region between the TP63 and LEPREL1 genes on chromosome 3q28, suggesting a role in the transcriptional regulation of these genes. In this study, we aimed to functionally characterize the 3q28 bladder cancer risk locus.
METHODS: Fine-mapping was performed by focusing on the region surrounding rs710521, and variants were prioritized for further experiments using ENCODE regulatory data. The enhancer activity of the identified region was evaluated using dual-luciferase assays. CRISPR/Cas9-mediated deletion of the enhancer region was performed and the effect of this deletion on cell proliferation and gene expression levels was evaluated using CellTiter-Glo and RT-qPCR, respectively.
RESULTS: Fine-mapping of the GWAS signal region led to the identification of twenty SNPs that showed a stronger association with bladder cancer risk than rs710521. Using publicly available data on regulatory elements and sequences, an enhancer region containing the bladder cancer risk variants was identified. Through reporter assays, we found that the presence of the enhancer region significantly increased ΔNTP63 promoter activity in bladder cancer-derived cell lines. CRISPR/Cas9-mediated deletion of the enhancer region reduced the viability of bladder cancer cells by decreasing the expression of ΔNTP63 and p63 target genes.
CONCLUSIONS: Taken together, our data show that bladder cancer risk-associated variants on chromosome 3q28 are located in an active enhancer region. Further characterization of the allele-specific activity of the identified enhancer and its target genes may lead to the identification of novel signaling pathways involved in bladder carcinogenesis.

Ankyloblepharon filiforme adnatum associated with Hay-Wells syndrome is a rare congenital disease caused by mutations in TP63 gene on the 3q27 chromosome. Here, we report a case of a new-born suffering from this syndrome in whom we detected a mutation c.1709T>C not previously included in the Ensemble database.
A girl delivered in the 34th week of gestation from a physiological pregnancy was born with extensive burn-like skin defects, ankyloblepharon filiforme adnatum, palate cleft, onychodystrophy of all limbs and syndactyly of toes. Hay-Wells syndrome was suspected and confirmed by genetic examination. A heterozygous missense change c.1709T>C was found in the TP63 gene. This variant leads to a 570th codon exchange of leucine for proline (p.Leu570Pro) on the protein level. The eyelid separation was performed surgically, burns were treated locally and cosmetic surgeries correcting other defects are planned for the near future. The girl is still monitored by a multidisciplinary team.
The mutation was not previously described in the literature or databases and should be included into these as probably pathogenic. A multidisciplinary approach is necessary to care for a patient with Hay-Wells syndrome, such care however can provide good results.

Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome is a disorder resulting from anomalous embryonic development of ectodermal tissues. There is evidence that AEC syndrome is caused by mutations in the TP63 gene, which encodes the p63 protein. This is an important regulatory protein involved in epidermal proliferation and differentiation.
Genome sequencing was performed in DNA from peripheral blood leukocytes of a newborn with AEC syndrome and her parents. Variants were searched in all coding exons and intron-exon boundaries of the TP63 gene.
A heterozygous missense variant (NM_003722.4:c.1063G>C (p.Asp355His) was found in the newborn patient. No variants were found in either of the parents.
We identified a previously unreported variant in TP63 gene which seems to be involved in the somatic malformations found in the AEC syndrome. The absence of this variant in both parents suggests that the variant appeared de novo.