TP63 – Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome

TP63, encoding the p63 transcription factor, is causally linked to autosomal dominant ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Monarch Initiative). AEC is characterised by eyelid adhesions, ectodermal dysplasia and orofacial clefting, with key features including ankyloblepharon (HP:0009755), ectodermal dysplasia (HP:0000968) and cleft palate (HP:0000175).

Inheritance is autosomal dominant with predominantly de novo missense and frameshift variants clustering in the sterile alpha motif (SAM) and transactivation inhibitory (TI) domains of p63. In a cohort of 19 unrelated probands from 12 families, 21 of 24 participants harboured TP63 mutations, with ≥70% of variants confirmed as de novo (PMID:19676060, PMID:22740388). Segregation analysis identified 5 additional affected relatives with fully penetrant, co-segregating variants.

The mutation spectrum includes missense substitutions, in-frame insertions and frameshifts. A representative pathogenic variant is c.1445T>C (p.Ile482Thr), located in the SAM domain, which abolishes critical protein–protein interactions and p63 function (PMID:30809829). Novel and recurrent alleles have been reported across diverse populations without evident founder effects.

Functional studies demonstrate that SAM domain mutations disrupt p63 transcriptional regulation and alternative splicing. The Q540L AEC-derived mutant impairs TAp63α transcriptional activity and misregulates genes controlling epidermal differentiation in stable cell lines (PMID:12446784). Additionally, AEC-associated SAM domain variants abrogate p63–ABBP1 interactions, altering FGFR2 splicing essential for epithelial maturation (PMID:12692135).

Mechanistically, AEC-linked TP63 variants act via dominant-negative and gain-of-function effects, leading to haploinsufficiency of epidermal differentiation pathways. Animal models and patient‐derived keratinocytes confirm disrupted wound healing and ectodermal development concordant with the human phenotype.

Overall, the clinical validity is Strong based on 19 probands in 12 families, frequent de novo occurrence and concordant functional assays. Genetic evidence is Strong (multiple variant types in SAM/TI domains, de novo in ≥70%). Functional evidence is Moderate (cellular assays and splicing studies consistently demonstrate pathogenic mechanisms).

Key Take-home: TP63 mutation analysis is essential for the accurate diagnosis and genetic counseling of AEC syndrome, guiding recurrence risk assessment and potential targeted therapies.

References

• American Journal of Medical Genetics Part A | 2009 | Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC). PMID:19676060
• American Journal of Medical Genetics Part A | 2012 | A novel de novo missense mutation in TP63 underlying germline mosaicism in AEC syndrome: implications for recurrence risk and prenatal diagnosis. PMID:22740388
• Molecular and Cellular Biology | 2002 | Complex transcriptional effects of p63 isoforms: identification of novel activation and repression domains. PMID:12446784
• The Journal of Biological Chemistry | 2003 | P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome. PMID:12692135

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