TP63 mutation mapping information in TP63 mutation-associated syndromes

Harazono, Yosuke; Morita, Keiichi; Tonouchi, Erina; Anzai, Eri; Takahara, Namiaki; Kohmoto, Tomohiro; Imoto, Issei; Yoda, Tetsuya

doi:10.1016/j.adoms.2022.100253

Cited by 2 publications

(3 citation statements)

References 52 publications

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“…The TP63 novel variant identified here is an excellent candidate for being the cause of the bilateral ectrodactyly in this patient, which has important clinical implications, suggesting that any change in this codon may have severe consequences developmentally. It is also an excellent candidate for being the cause of the patient's oral cleft since this fits the pattern of TP63 ‐Related Disorders (Harazono et al, 2022 ) and similar phenotypes observed in individuals with other mutations in the same codon of TP63 . However, it is possible that this de novo variant is not the cause of the patient's bilateral cleft lip and palate given his uncle's cleft lip and palate and biological relationship of his parents.…”

Section: Discussionsupporting

confidence: 61%

“…Incomplete penetrance has also been observed in a small number of individuals and pedigrees (Amiel et al, 2001 ; Spranger & Schapera, 1988 ). Genotype–phenotype analyses have shown the link between the various clinical presentations of TP63 related disorders (Alves et al, 2015 ; Harazono et al, 2022 ). The R319L mutation reported here appears novel, with no recorded instances in public variation or clinical databases.…”

Section: Discussionmentioning

confidence: 99%

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A novel de novo TP63 mutation in whole‐exome sequencing of a Syrian family with Oral cleft and ectrodactyly

Simpson,

Kimble,

Chandrasekharappa

et al. 2023

Molec Gen & Gen Med

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BackgroundOral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole‐exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly but not ectodermal dysplasia as typically seen in ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome‐3. A paternal uncle with only an oral cleft was deceased and unavailable for analysis.MethodsVariant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing, and pathogenicity assessed by knocking out the tp63 gene in zebrafish to evaluate its role during zebrafish development.ResultsTwenty‐eight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G > T, p.Arg319Leu), and confirmed by Sanger sequencing.ConclusionTP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. Two known mutations in the same codon (c.956G > A, p.(Arg319His; rs121908839, c.955C > T), p.Arg319Cys) cause ectrodactyly, providing evidence that mutating this codon is deleterious. While this TP63 mutation is the best candidate for the patient's clinical presentation, whether it is responsible for the entire phenotype is unclear. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days post‐fertilization (dpf). The embryonic phenotype could not be rescued by injection of zebrafish or human messenger RNA (mRNA). Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

A novel de novo TP63 mutation in whole‐exome sequencing of a Syrian family with Oral cleft and ectrodactyly

Simpson,

Kimble,

Chandrasekharappa

et al. 2023

Molec Gen & Gen Med

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“…There is strong evidence from human and mouse studies for the TP63 transcription factor involvement in tooth development. Mutations of this gene have been associated with six autosomal dominant syndromes characterized mainly by ectodermal dysplasia, limb malformation and OFC [ 49 ]. Dental anomalies in these disorders are common and include TA, conoid teeth, taurodontism, enamel hypoplasia and dentinal dysplasia [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Biedziak

Firlej

Dąbrowska

et al. 2022

JCM

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Non-syndromic tooth agenesis (ns-TA) is one of the most common dental anomalies characterized by the congenital absence of at least one permanent tooth (excluding third molars). Regarding the essential role of genetic factors in ns-TA aetiology, the present study aimed to identify novel pathogenic variants underlying hypodontia and oligodontia. In a group of 65 ns-TA patients and 127 healthy individuals from the genetically homogenous Polish population, the coding sequences of 423 candidate genes were screened using targeted next-generation sequencing. Pathogenic and likely pathogenic variants were identified in 37 (56.92%) patients, including eight nucleotide alternations of genes not previously implicated in ns-TA (CHD7, CREBBP, EVC, LEF1, ROR2, TBX22 and TP63). However, since only single variants were detected, future research is required to confirm and fully understand their role in the aetiology of ns-TA. Additionally, our results support the importance of already known ns-TA candidate genes (AXIN2, EDA, EDAR, IRF6, LAMA3, LRP6, MSX1, PAX9 and WNT10A) and provide additional evidence that ns-TA might be an oligogenic condition involving the cumulative effect of rare variants in two or more distinct genes.

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TP63 mutation mapping information in TP63 mutation-associated syndromes

Cited by 2 publications

References 52 publications

A novel de novo TP63 mutation in whole‐exome sequencing of a Syrian family with Oral cleft and ectrodactyly

A novel de novo TP63 mutation in whole‐exome sequencing of a Syrian family with Oral cleft and ectrodactyly

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

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