Achondroplasia via the FGFR3 Gene, Exon 10

Achondroplasia (OMIM#100800) is the most common form of inherited disproportionate short stature. It occurs in 1 in 15,000 to 1 in 40,000 live births. Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features with frontal bossing and mid-face hypoplasia (Francomano. GeneReviews. 2006). This condition can be diagnosed by characteristic clinical and radiographic findings in most affected individuals.

Achondroplasia is inherited in an autosomal dominant manner with complete penetrance. Over 80% of individuals with achondroplasia have parents with normal stature and have achondroplasia as the result of a de novo variant. More than 99% of individuals with achondroplasia have one of two variants in exon 10 of the FGFR3 gene. In about 98% of individuals, the variant is c.1138G>A, and in about 1% of individuals, the variant is c.1138G>C, both resulting in a p.Gly380Arg substitution in the FGFR3 protein (Shiang et al. Cell 78:335–342, 1994; Bellus et al. Am J Hum Genet 56:368–373, 1995). One other amino acid substitution (p.Gly375Cys) encoded within FGFR3 exon 10 has also been reported to cause this condition (Ikegawa et al. Hum Genet 96:309-311, 1995).  The FGFR3 gene encodes fibroblast growth factor receptor-3, a member of the FGFR family. Like all of the FGFRs, FGFR3 is a membrane-spanning tyrosine kinase receptor with an extracellular ligand-binding domain consisting of three immunoglobulin subdomains, a transmembrane domain, and a split intracellular tyrosine kinase domain (Green et al. Bioessays 18:639–646. 1996). The p.Gly380Arg variant, located in the transmembrane domain, has been shown to result in constitutive activation of the FGF receptor (Deng et al. Cell 84:911–921, 1996).

This test is predicted to detect disease variants in >99% of affected individuals (Shiang et al. 1994, Bellus et al. 1995).

This test involves bidirectional sequencing of the target coding exon (exon 10) of the FGFR3 gene using genomic DNA. The full coding region of the selected exon plus ~10 bp of flanking non-coding DNA on each side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known variant or to confirm research results.