Submission Details

MSX1 was first reported in relation to autosomal dominant tooth and nail syndrome in 2001 (Jumlongras et al., PMID: 11369996). MSX1 has been noted to be associated with the following disease entities: Orofacial cleft 5 (OMIM:608874), Tooth agenesis, selective, 1, with or without orofacial cleft (OMIM:106600) and Ectodermal dysplasia 3, Witkop type (OMIM:189500). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in phenotypic variability therefore, Ectodermal dysplasia 3, Witkop type (OMIM:189500) also known as tooth and nail syndrome was split. Whereas, the following disease entities Orofacial cleft 5 (OMIM:608874) and Tooth agenesis, selective, 1, with or without orofacial cleft (OMIM:106600) have been lumped into one disease entity, tooth agenesis, selective, 1 (MONDO:0007129). This curation is for the split entity autosomal dominant tooth and nail syndrome. Three variants (1 nonsense, 1 3’UTR, 1 missense) that have been reported in 3 probands in 3 publications (PMIDs: 11369996, 24031111, 33708320) are included in this curation. However, the genetic evidence was not scored due to uncertainty of phenotypes illustrated in the study, frequency of variants and/or poor in silico scores. The mechanism of pathogenicity is unknown. This gene-disease association is supported by experimental evidence including expression in the nail bed and hair follicles of mice (PMID: 7538067) and an MSX1 knockout mice showing defective nail plates (PMID: 11369996). In summary, the evidence supporting the relationship between MSX1 and autosomal dominant tooth and nail syndrome has been disputed and no valid genetic evidence remains to support the claim. More evidence is needed to either support or entirely refute the role MSX1 plays in this disease.This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting dates 10/19/23 and 02/08/2024 (SOP Version 9).