Submission Details

FGF9 was first reported in relation to autosomal dominant multiple synostoses syndrome in 2009 (Wu et al., PMID: 19589401). This condition is characterized by many synostoses, including sagittal craniosynostosis, as well as synostoses of elbows, hands, feet, and lumbar vertebrae. The condition also includes other skeletal anomalies (pectus excavatum, joint stiffness, recurrent sprains), crowded teeth, and cleft palate. 6 variants that have been reported in at least 20 probands in 6 publications (PMIDs: 19589401, 28730625, 33140402, 33174625, 35316564, 36980996) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (2 mouse models, expression-level evidence, interaction evidence; PMIDs: 11165488, 19219044, 21402782, 22123828, 28169396). Mouse models show that mutant mice have abnormal osteogenesis of coronal sutures, atypical expression of skeletal-related genes in the elbow joint, and joint fusions. Expression-level evidence shows expression in the palatal bone and the midfacial region. The gene is also shown to interact with TGFBR1 (ALK5) and TGFBR2, both of which are definitively associated with Loeys-Dietz Syndrome, which includes craniofacial features (bifid uvula, cleft palate, malar flattening, hypertelorism, strabismus, retrognathia) and skeletal features (joint dislocation/laxity, pectus excavatum, scoliosis, talipes equinovarus, pes planus). An important note is that none of the probands scored in this FGF9 curation have cardiac issues, which are a feature of Loeys-Dietz Syndrome. In summary, there is definitive evidence to support the relationship between FGF9 and autosomal dominant multiple synostoses 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 GCEP on the meeting date 6/24/2025 (SOP Version 11).