OBJECTIVE: Mutations of the fibroblast growth factor receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion. DESIGN: A three-generation family A with dominantly transmitted proportionate short stature was studied by whole-exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family B with dominant proportionate short stature and identified a rare variant in FGFR3. METHODS: Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants. RESULTS: A novel p.M528I mutation in FGFR3 was detected in family A, which segregates with short stature and proved to be activating in vitro. In family B, a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared with WT. CONCLUSIONS: Proportionate short stature can be caused by a mutation in FGFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.

Department of Clinical GeneticsLeiden University Medical Center PO Box 9600 2300RC Leiden The NetherlandsDepartment of BiologyFaculty of MedicineCentral European Institute of TechnologyMasaryk University Brno Czech RepublicDepartment of PediatricsLeiden University Medical Center Leiden The NetherlandsDepartment of Internal MedicineErasmus Medical Center Rotterdam The NetherlandsDepartment of Orthopaedic SurgeryDavid Geffen School of Medicine at UCLA Los Angeles California USA

Department of Clinical GeneticsLeiden University Medical Center PO Box 9600 2300RC Leiden The NetherlandsDepartment of BiologyFaculty of MedicineCentral European Institute of TechnologyMasaryk University Brno Czech RepublicDepartment of PediatricsLeiden University Medical Center Leiden The NetherlandsDepartment of Internal MedicineErasmus Medical Center Rotterdam The NetherlandsDepartment of Orthopaedic SurgeryDavid Geffen School of Medicine at UCLA Los Angeles California USA Department of Clinical GeneticsLeiden University Medical Center PO Box 9600 2300RC Leiden The NetherlandsDepartment of BiologyFaculty of MedicineCentral European Institute of TechnologyMasaryk University Brno Czech RepublicDepartment of PediatricsLeiden University Medical Center Leiden The NetherlandsDepartment of Internal MedicineErasmus Medical Center Rotterdam The NetherlandsDepartment of Orthopaedic SurgeryDavid Geffen School of Medicine at UCLA Los Angeles California USA

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