The NECTIN1 gene is located at chromosome 11q23.3, and encodes an adhesion protein that plays a role in the organization of adherens and tight junctions in epithelial and endothelial cells. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: Cleft lip/palate-ectodermal dysplasia syndrome (MIM:225060) and Orofacial cleft 7 (MIM:225060). Here, we curate autosomal recessive cleft lip/palate-ectodermal dysplasia syndrome (http://purl.obolibrary.org/obo/MONDO_0009151).
NECTIN1 was reported in connection with autosomal cleft lip/palate-ectodermal dysplasia syndrome in 2000 (Suzuki et al., 2000 PMID: 10932188). Five protein truncating mutations (3 nonsense, 2 frameshift) reported in three publications have been included in this curation (PMIDs: 25913853, 10932188, 34556655). Molecular mechanism of pathogenicity appears to be loss-of-function whereby homozygous NECTIN1 molecular defects are predicted to disrupt the protein-protein interactions needed to initiate the cell-cell adhesion process (PMID: 25913853). Parental consanguinity and the unique clinical features may differentiate this syndrome from other disease assertions, therefore the expert panel decided to not reduce the scores of probands with established or suspected consanguineous parents. The maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression studies, protein interaction, and a mouse model.
In summary, there is definitive evidence supporting the relationship between NECTIN1 and autosomal recessive cleft lip/palate-ectodermal dysplasia syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 06/20/2024 (SOP Version 10).
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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