TFAP2B is located on chromosome 6 at 6p12.3 and encodes the transcription factor AP-2β protein which is part of a family of AP-2 transcription factors, all of which play a role in development. Multiple disease entities have been reported in association with this gene: Char syndrome (MIM:169100), patent ductus arteriosus 2 (PDA) (MIM:617035), and syndromic craniosynostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in molecular mechanism and inheritance pattern between Char syndrome and PDA. Therefore, the following disease entities have been lumped into one disease entity: TFAP2B- related congenital heart disease spectrum disorder (MONDO:1010098). The syndromic craniosynostosis assertion has been split and will be curated when additional genetic evidence is published.
TFAP2B was first reported in connection with autosomal dominant TFAP2B- related congenital heart disease spectrum disorder in 2000 (Satoda et al. 2000 PMID: 10802654). The disorder is characterized by PDA, facial dysmorphism (wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge and upturned nasal tip, short philtrum with a triangular mouth, and thickened, everted lips), hand anomalies (aplasia or hypoplasia of the middle phalanges of the fifth fingers). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Twelve variants (7 missense, 3 splice site, 2 frameshift) reported in 12 probands in seven publications have been included in this curation (PMIDs: 10802654,15684060, 21643846,30579973,18752453, 11505339, 31012281). This gene-disease relationship is also supported by expression data, biochemical function studies, and two non-human model organisms (PMIDs: 21829553, 32878901, 8989526). In summary, there is definitive evidence supporting the relationship between TFAP2B and TFAP2B- related congenital heart disease spectrum disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 2nd, 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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