Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Fibroblast growth factor receptor 3 (FGFR3) is a tyrosine kinase receptor whose gain-of-function variants underlie several skeletal dysplasias. Camptodactyly-tall stature-scoliosis-hearing loss syndrome (MONDO:0012504) is a rare autosomal dominant condition characterised by bilateral camptodactyly, disproportionate tall stature, progressive scoliosis and sensorineural hearing loss.
In 2016, the second unrelated family with CATSHL was reported, identifying two affected individuals harbouring heterozygous FGFR3 missense variants c.1861C>T (p.Arg621Cys) and c.1862G>A (p.Arg621His) that segregated with full penetrance in an autosomal dominant pattern (PMID:27139183). Combined with the original report, at least two families and two probands support a consistent gene–disease relationship (PMID:27139183).
Both variants affect adjacent residues within the FGFR3 kinase domain, likely altering receptor conformation and downstream MAPK/STAT signalling. No additional recurrent or founder alleles have been described, and allele frequencies remain unreported given the extreme rarity of CATSHL.
Pathogenic mechanisms for FGFR3-related skeletal disorders commonly involve constitutive kinase activation. Although functional studies specific to CATSHL variants are lacking, analogous activation loop mutations in FGFR3 exhibit gain-of-function effects, providing mechanistic plausibility for the CATSHL-associated variants.
To date, no conflicting data have been published, and all reported FGFR3 variants in CATSHL are absent in unaffected relatives and population databases. Molecular testing of FGFR3 should be considered in patients presenting with the characteristic CATSHL phenotype.
Key Take-home: Heterozygous FGFR3 missense gain-of-function variants cause CATSHL syndrome with consistent autosomal dominant inheritance, supporting targeted diagnostic testing and informing future functional studies.
Gene–Disease AssociationModerateTwo unrelated families with specific FGFR3 missense variants segregating with CATSHL syndrome (2 probands) ([PMID:27139183]) Genetic EvidenceModerate2 probands from 2 families with autosomal dominant inheritance, variant segregation confirmed ([PMID:27139183]) Functional EvidenceLimitedNo direct functional studies of FGFR3 variants in CATSHL syndrome; mechanism inferred from FGFR3 activation in related disorders |