TBX22 was first reported in relation to X-linked cleft palate with/without ankyloglossia in 2001 (Braybrook et al., PMID: 11559848 ). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Abruzzo-Erikson syndrome (OMIM:302905) and cleft palate with ankyloglossia (OMIM:303400). 9 variants (missense, nonsense, frameshift, splicing) that have been reported in over 30 probands in 5 publications (PMIDs: 11559848, 14729838, 22784330, 29932061, 30462376) are included in this curation. The phenotypes of some of the affected families were reported in earlier publications (PMIDs: 839509, 1570839), before TBX22 was discovered as the causative gene. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence; PMIDs: 19648291, 20845426). The mouse model shows that mutant mice exhibit ankyloglossia and submucous cleft palate. Expression-level data in mice embryos show expression of the gene in the palatal bone. In summary, there is definitive evidence supporting the relationship between TBX22 and X-linked cleft palate with/without ankyloglossia. 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 9/19/2024 (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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