FGFR2 has been repeatedly described in association with autosomal dominant Apert Syndrome which is characterized by craniofacial anomalies and syndactyly of the hands and feet. FGFR2-related Apert Syndrome is primarily caused by two gain-of-function missense variants, the p.Ser252Trp variant which leads to more severe craniofacial phenotypes, and the p.Pro253Arg variant which leads to more severe syndactyly (Wilkie et al. 1995; PMID: 7719344). These two missense variants, an indel, and an Alu insertion have been reported in at least 15 probands from 9 publications (PMIDs: 33585639, 9002682, 9973282, 28316926, 10658283, 9452027, 29483804, 21943124, 18726952). This gene-disease association is also supported by experimental evidence including an animal model, and an assay showing increased binding of variant FGFR2 with FGF ligands (PMIDs: 23495236, 11390973). In summary, FGFR2 is definitively associated with autosomal dominant Apert Syndrome. 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 Gene Curation Expert Panel on 8/19/2021. Gene Clinical Validity Standard Operating Procedures (SOP) – Version 8.
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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