TP63 was first reported in relation to AD TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations in 1999 (Celli et al., PMID: 10535733). TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations is characterized by variable ectodermal dysplasia, limb defects, and orofacial clefting. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern and phenotypic variability. Therefore, the following disease entities, EEC3 syndrome (MIM:604292), ADULT syndrome (MIM:103285), AEC syndrome (MIM:106260), Rapp-Hodgkin syndrome (MIM:129400), Limb-mammary syndrome (MIM:603543), Split-hand/foot malformation 4 (MIM:605289), and Orofacial cleft 8 (MIM:618149), have been lumped into one disease entity, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations. However, Premature ovarian failure 21 (MIM:620311) was split out due to phenotypic differences and will be curated by a different GCEP.
21 variants (16 missense, 4 frameshift, and 1 nonsense) that have been reported in 21 probands in 9 publications (PMIDs: 10535733, 11159940, 11462173, 20491771, 21204238, 22574117, 29500247, 33622322, 37920856) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity at this time is unknown. This gene-disease relationship is also supported by animal models, functional alteration, protein-protein interactions, and expression studies (PMIDs: 10227294, 22247000, 19353588, 20855944, 21965674). In summary, there is definitive evidence supporting the relationship between TP63 and AD TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Craniofacial Malformation GCEP on the meeting date October 17th, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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