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 the likely causal FGF4 retrogene.

Brown et al. (2017) reported that a "genome-wide association analysis of Hansen’s type I IVDD [see OMIA 000157-9615] across breeds localized . . . [a] 1.9-Mb region on CFA12 [exactly the same region to which these same authors had mapped skeletal dysplasia in Nova Scotia Duck Tolling retrievers, NSDTR; see OMIA 002133-9615], suggesting that the locus responsible for SD in the NSDTR is also responsible for type I IVDD and the chondrodystrophoid phenotype across dog breeds".

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. Because the retrogene is not included in NCBI's Gene database, the table below lists the normal FGF4 gene.

As noted by Brown et al. (2017), despite its obvious importance, the above insertion variant "failed to explain breeds such as the American cocker spaniel, beagle, and French bulldog, that in addition to dachshunds, were the breeds originally classified as chondrodystrophoid based on histopathologic and morphologic analysis" by Hansen (1951, 1952) and Braund et al. (1975).

Within their candidate region on CFA12 (see Mapping section above), Brown et al. (2017) identified a likely causal variant, namely an FGF4 retrogene insertion in chromosome CFA12 (12: g.33710178_33710179insMF040221.1; CanFam3), . . . the insertion on CFA12 is 3,209 bp long (GenBank accession no. MF040221) and includes parental FGF4 cDNA (i.e., FGF4 exons spliced without introns) . . . . The insert also contains a majority of the predicted 5′-untranslated region (UTR), which includes the transcription start site (TSS) as only PCR primers FGF4_TSS.F1 and FGF4.R1 yielded a product in RT-PCR using cDNA from neonatal beagle IVD . . . . The insertion location is intergenic between the 3′-UTR of OGFRL1 ∼9.5 kb on the proximal side and ∼350 kb to the RIMS1 gene on the distal side."

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".

Breeds: Basset Hound, Dachshund, Pembroke Welsh Corgi.

Associated gene: