MSX1 was first reported in relation to autosomal dominant tooth agenesis, selective, 1 in 1996 (Vastardis et al., PMID: 8696335). 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) 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). The split disease entity will be curated separately. This curation is for the lumped entity autosomal dominant tooth agenesis, selective, 1. Ten variants (5 missense, 4 nonsense, 1 frameshift) that have been reported in 10 probands in 6 publications (PMID: 8696335, 12097313, 15264286, 33419968, 10742093, 22813217) 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 is reported to be loss of function. This gene-disease association is also supported by experimental evidence such as protein-protein interaction and expression level evidence (PMID: 16651263, 16651263). Additionally, MSX1 knockout mice had phenotypes including cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development (PMID: 7914451). In summary, MSX1 is definitively associated with autosomal dominant tooth agenesis, selective, 1. 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 Malformations GCEP on the meeting date 10/19/23 (SOP Version 9).
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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