AI Article Synopsis
- Mutations in the FGFR3 gene can lead to various forms of short stature, including hypochondroplasia, but routine testing for these mutations is not done for children without disproportionate short stature.
- A family study using whole-exome sequencing identified a novel FGFR3 mutation (p.M528I) linked to short stature, while a second family had a rare variant (p.F384L) that did not correlate with this condition.
- The findings suggest that testing for FGFR3 mutations should be considered for individuals with proportionate short stature, particularly when there's a history of autosomal dominant inheritance, but additional functional tests are crucial to confirm pathogenicity.
Article Abstract
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.
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| http://dx.doi.org/10.1530/EJE-14-0945 | DOI Listing |
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