In other species: crab-eating macaque , Rhesus monkey , domestic cat , lion , tiger , horse , taurine cattle , sheep , rabbit

Categories: Skeleton phene (incl. short stature & teeth)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Cross-species summary: Also known as calcification of intervertebral discs.

Species-specific name: Intervertebral disc disease; Hansen type I / acute intervertebral disc extrusion

Species-specific symbol: IVDD

Species-specific description: "Two FGF4 retrogenes (FGF4L1 on chromosome 18 and FGF4L2 on chromosome 12) have been identified to cause dwarfism across many dog breeds. Some breeds are nearly homozygous for both retrogenes (e.g., Dachshunds) and others are homozygous for just one (e.g., Beagles and Scottish Terriers)" (Bannasch et al., 2022)

History: As summarised by Brown et al. (2017): "Hansen [1951, 1952] described the two different types of canine IVD prolapse as type I and type II. Type I occurs exclusively in chondrodystrophic breeds [e.g. "basset hound, Pembroke Welsh corgi, and dachshund"] and is characterized by premature degeneration of all discs in young dogs. In contrast, type II occurs in older dogs and is usually limited to a single disc with only partial protrusion."

Inheritance: Brown et al. (2017): "IVDD-affected NSDTRs were also all either homozygous or heterozygous for the CFA12 FGF4 insertion. This supports the idea that while the CFA12 FGF4 insertion is semidominant with respect to height, it is dominant for altered IVDs" Bannasch et al. (2022): "Using individual measurements of height at the shoulder, back length, head width, thorax depth and width, and thoracic limb measurements, we evaluated the combined effects of FGF4 retrogenes [FGF4L1 and FGF4L2] within" two breeds that segregate both retrogenes, namely Alpine Dachsbracke and the Schweizer Niederlaufhund. They found that "both retrogenes had significant effects reducing height at the shoulders and antebrachial length, with FGF4L1 having a much greater effect than FGF4L2. FGF4L1 alone influenced the degree of carpal valgus and FGF4L2 alone increased head width. Neither retrogene had an effect on thorax width or depth." From a detailed analysis of 569 surgical cases of IVDD, Batcher et al. (2019) concluded that "The FGF4 retrogene on CFA12 acts in a dominant manner to decrease the age of onset and increase the overall risk of disc disease in dogs. Other modifiers of risk may be present within certain breeds, including the FGF4 retrogene on CFA18."

Mapping: From a GWAS on 48 affected and 46 control Dachsunds, each genotyped with the Illumina CanineHD BeadChip, yielding "> 109,000" SNPs, Mogensen et al. (2011) "identified a locus on chromosome 12 from 36.8 to 38.6 Mb with 36 markers reaching genome-wide significance (P(genome) = 0.00001-0.026)". Mogensen et al. (2012) "validated the association of the chromosome 12 locus with disk calcification in an independent sample of wire-haired Dachshunds and identify potential risk variants." They also "estimated haplotype effects and set up a model for prediction of disk calcifications in wire-haired Dachshunds based on genotype data." Brown et al. (2017) reported that a "genome-wide association analysis of Hansen’s type I IVDD across breeds [mapped this disorder to 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: Brown et al. (2017) reported that an FGF4 retrogene insertion in chromosome CFA12 (12: g.33710178_33710179insMF040221.1; CanFam3) is "responsible for type I IVDD . . . across dog breeds . . . 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." Because the retrogene is not included in NCBI's Gene database, the table below lists the normal FGF4 gene.

Clinical features: Batcher et al. (2019) concluded that "The FGF4 retrogene on CFA12 acts in a dominant manner to decrease the age of onset and increase the overall risk of disc disease in dogs. Other modifiers of risk may be present within certain breeds, including the FGF4 retrogene on CFA18." In Nova Scotia Duck Tolling Retrievers, Murphy et al. (2019) concluded that dogs with the retrogene variant present with clinical signs "consistent with premature chondroid degeneration of the intervertebral disc and suggest that the presence of the CFA12 FGF4 retrogene is sufficient to cause the chondrodystrophic phenotype."

Control: Bruun et al. (2020) concluded that "Our results show that the FGF4 retrogene insertion on CFA12 is not a valid risk indicator on its own. Relying on the DNA test will have an irreversible effect on the Dachshund breed excluding almost all dogs from breeding. Thus, using calcification status remains the most reliable breeding scheme for disc herniation in Dachshunds." Bannash et al. (2022) recommend that "Selectively breeding dogs with FGF4L1 and without FGF4L2 would likely lead to a reduction in the FGF4L2-related risk of intervertebral disc herniation while maintaining the reduction in leg length resulting from FGF4L1."

Breeds: American Cocker Spaniel (Dog) (VBO_0200038), Basset Hound (Dog) (VBO_0200126), Beagle (Dog) (VBO_0200131), Cardigan Welsh Corgi (Dog) (VBO_0200290), Cavalier King Charles Spaniel (Dog) (VBO_0200309), Chesapeake Bay Retriever (Dog) (VBO_0200326), Chihuahua (Dog) (VBO_0200338), Coton de Tulear (Dog) (VBO_0200389), Dachshund (Dog) (VBO_0200406), English Springer Spaniel (Dog) (VBO_0200497), French Bulldog (Dog) (VBO_0201455), Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964), Pekingese (Dog) (VBO_0200994), Poodle, Miniature (Dog) (VBO_0201051), Poodle, Toy (Dog) (VBO_0201061), Shih Tzu (Dog) (VBO_0201223).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: