FGFR3 was first reported in relation to AD thanatophoric dysplasia in 1995 (Tavormina et al., PMID: 7773297). Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and redundant skin on the arms and legs. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities (thanatophoric dysplasia, type I, MIM:187600 and thanatophoric dysplasia, type II, MIM:187601) have been lumped into one disease entity, thanatophoric dysplasia. The split curations for SADDAN, CATSHL, hypochondroplasia, and achondroplasia have been curated separately.
3 missense, 3 stop-loss, and one indel variants that have been reported in 19 probands in 5 publications (PMIDs: 7773297, 7647778, 19752524, 29458880, 27028100) 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 disease is reported to be gain of function. This gene-disease association is also supported by experimental evidence including mouse models and functional assays in a cell line and patient cells (PMIDs: 10861287, 9069288, 9438390). In summary, there is definitive evidence supporting the relationship between FGFR3 and AD thanatophoric dysplasia. 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 Skeletal Disorders GCEP on the meeting date January 13th, 2022 (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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.