In other species: domestic cat , pig , cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 225500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2009

Cross-species summary: Abnormal growth of cartilage, leading to disproportionate dwarfism.

Mapping: In a mammoth GWAS on 95 chondrodysplastic dogs from 8 breeds and 702 non-chondrodysplastic dogs from 64 breeds, each genotyped with the Affymetrix version 2.0 SNP chip (yielding 41,635 informative SNPs for analysis), Parker et al. (2009) highlighted a 431kb region on chromosome CFA18.

By conducting a proof-of-principal across-breed GWAS on 18 affected (from 6 breeds, and including 3 crossbred dogs) and 27 control dogs from 11 breeds (and including 4 crossbred dogs), each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) highlighted the same region on chromosome CFA18 that had been shown by Parker et al. (2009) to harbour a likely causal FGF4 retrogene.

For the mapping of a similar phenotype in other breeds to a likely causal variant on chromsome CFA18, see Brown et al. (2017) in OMIA 000157-9615.

Molecular basis: Sequencing within the candidate region (see Mapping section) by Parker et al. (2009) revealed the likely causal mutation to be a 5kb insertion containing a FGF4 retrogene, i.e. a processed pseudogene of FGF4: "Neither the introns nor the upstream promoter sequences of the gene were present in the insert, however all exons were present, with no alterations in the coding sequence, as well as the 3’ UTR and poly-A tail characteristic of retrotransposition of processed mRNA". Furthermore, "The retrogene is inserted in the middle of a LINE with both LINEs and SINEs upstream". The authors suggested "that atypical expression of the [retrogen] FGF4 transcript in the chondrocytes may be causing inappropriate activation of one or more of the fibroblast growth factor receptors such as FGFR3", mutations in which account for the majority of dwarfism cases in humans. The insertion containing the FGF4 retrogene starts at 23,431,136 on CFA18, which is 25Mb away from the complete FGF4 gene, which is located at 48413479-48415205.

Clinical features: Even though chondrodysplasia is normally regarded as a defect, this canine mutation is not classified as a defect because, as noted by Parker et al. (2009), it is a "a short-legged phenotype that defines at least 19 dog breeds including dachshund, corgi, and basset hound".

Prevalence: Parker et al. (2009) reported that the CFA18 FGF4 retrogene insertion is fixed (i.e. freq = 1) in the 15 chondrodysplastic breeds listed below.

Breeds: Basset Hound, Cairn Terrier, Cardigan Welsh Corgi, Dachshund, Dandie Dinmont Terrier, Lancashire heeler, Norwich Terrier, Pekingese, Pembroke Welsh Corgi, Petit Basset Griffon Vendéen, Shih-Tzu, Skye Terrier, Swedish Vallhund, Tibetan spaniel, West Highland Terrier.