CDDY with IVDD risk and CDPA
The dwarfism of many short-legged dog breeds is due to the FGF4 retrogenes on:
- Chromosom 18 (FGF4-L1) and
- Chromosom 12 (FGF4-L2).
In breeds with particularly short legs (Dachshund, Basset, Corgi, Skye Terrier) both retrogenes are present, whereby they are largely fixed as the basis of the breed standard.
In molecular genetics, this is expressed in predominantly purebred (homozygous) genes; mixed-breed animals are rare. If such heterozygous animals mate, offspring purebred for the wild-type, are possible.
The FGF4-L1 retrogene leads to a developmental disorder with malformations of the cartilage (chondrodysplasia - CDPA). The main effect is the shortening of the limbs, without any associated health problems. In mixed-breed animals, the shortening is less pronounced.
The effect of FGF4-L2 is a chondrodystrophy (CDDY), whereby the composition of the cartilage tissue is disturbed. In addition to the dose-dependent shortening of the limbs, it is accompanied by an early degeneration of the intervertebral discs, also dose-dependent.
In certain breeds, the presence of FGF4-L2 is considered a predisposition to the development of IVDD type 1 (IVDD = Intervertebral Disc Disease, “herniated disc”).
Occurrence and frequency of FGF4-L1 and FGF4-L2
A study on the occurrence of the two FGF4 retrogenes in different breeds can be found in: Embersics et al., 2024 (Link). An excerpt from this:
| Breed | FGF4-L2 | % FGF4-L1 |
| Dachshund | 95% | 98% |
| Basset Hound | 79% | 89% |
| Pembroke Welsh Corgi | 84% | 98% |
| Skye Terrier | 77% | 100% |
| French Bulldog | 92% | 0% |
| English Cocker Spaniel | 96% | 0% |
| Poodle (Minature, Toy) | 60% | 11% |
| Poodle Standard | 10% | 0% |
| Nova Scotia Duck Tolling Retriever | 35% | 0% |
| Golden Retriever | 6% | 0% |
| Airdale Terrier | 5% | 0% |
Clinical significance of CDPA | CDDY -IVDD - Intervertebral Disk Disease
CDPA is inherited in an autosomal dominant manner, so that a single FGF4-L1 gene is sufficient to cause shortened limbs. In most breeds, however, other factors/genes contribute to the final expression of the phenotype. In the very short-legged breeds, this is mainly FGF4-L2.
The FGF4-L1 gene is also known as the CD locus.
The extent to which FGF4-L2-related CDDY contributes to shortening of the limbs and promotes the development of IVDD type 1 depends largely on the individual breeds.
For example, dogs of the Nova Scotia Duck Tolling Retriever breed, in which FGF4-F1 does not occur, show a strong association between the presence of FGF4-L2 and the occurrence of IVDD. (Bianchi et al., 2023).
In dog breeds in which FGF4-L2 is largely fixed, such as Dachshunds, there is a higher rate of IVDD cases, but these cannot be explained by the presence of FGF4-L2 due to the disproportion between clinical occurrence (4-20% depending on breed and country) and the frequency of FGF4-L2 (>95%).
It is assumed that these breeds were formed by animals that have unknown genetic traits that can largely compensate for the harmful effect on the intervertebral discs.
Clinical differentiation of IVDD type 1 and IVDD type 2
IVDD type 1
- Degeneration and calcification of all intervertebral discs occur even in young dogs.
- As a result of the loss of elasticity, the outer fibrous ring that surrounds the gelatinous core of an intervertebral disc can tear.
- The tear causes the contents of the intervertebral disc to burst out and press on the spinal cord.
- Type 1 therefore has an acute course with sudden onset of pain and paralysis.
IVDD type 2
- In IVDD type 2 the outer fibrous ring of the intervertebral discs loses its strength and the gelatinous core presses the fibrous ring on the spinal cord.
- This leads to pain and paralysis.
- The symptoms develop gradually and increase over time.
- The persistent pressure impairs the blood supply and often leads to permanent nerve damage.
- Usually only individual intervertebral discs are affected.
- Currently it lacks a mutation test for IVDD type 2.
Breeds affected by IVDD type 1
Below a list of the breeds in which, according to Brown et al (2017), the mutation segregates with the occurrence of type 1 disc herniation. However, it should be noted that these studies are based on populations in the USA/North America and cannot be easily transferred to other populations.
A more recent study (Bruun et al, 2020) came to the conclusion that a test for FGF-L2 as a risk factor for the development of IVDD type 1 in Dachshunds is not meaningful. Therefore 'Dachshund' was removed from the list of Brown et al. you find below.
- American Cocker Spaniel
- Basset Hound
- Beagle
- Cardigan Welsh Corgi
- Chesapeake Bay Retriever
- Chihuahua
- Coton de Tulear
- English Springer Spaniel
- French Bulldog
- Jack Russel Terrier
- Miniature Schnauzer
- Nova Scotia Duck Tolling Retriever
- Pekinese
- Pembroke Welsh Corgi
- Poodle (Miniature)
- Portuguese Water Dog
- Scottish Terrier
- Shih Tzu
Test recommendations
Dachshund, Basset, Corgi, Skye Terrier
The test for FGF4-L2 [CDDY - IVDD] is not suitable for determining the risk of developing IVDD due to the extensive fixation of the trait.
The test can be used to specifically search for animals that are heterozygous for FGF4-L2 or even homozygous for the wild type allele lacking FGF4-L2 completely. These animals have longer limbs compared to animals with homozygous FGF4-L2 traits.
The test for FGF4-L1 (CDPA) can be used like the test for FGF4-L2, to search for animals that may be heterozygous for FGF4-L1.
FGF4-L1 is considered to be the essential genetic basis for the development of the breed-typical stature of Dachshunds and is therefore largely homozygous (98% allele frequency).
Genotype and laboratory findings for CDDY with IVDD risk
Inheritance: autosomal-semi-dominant for CDDY / incomplete autosomal-dominant for IVDD
The dog has shortened legs (CDDY), the length of which depends on the number of copies of the mutation. In some breeds the risk of developing IVDD type 1 is increased if one copy (n/CDDY) or both copies of the gene (CDDY/CDDY) are affected by the mutation. Dogs that do not have a copy of the causative mutation (n/n) do not have an increased susceptibility to type 1 disc herniation.
Risk
The test examines whether the dog carries the insertion of the FGF4 retrogene on chromosome 12. With the data currently available, it is not yet possible to measure the individual animal's absolute risk of actually developing IVDD.
Genotypes:
n/n = genetically normal
The dog does not have shortened legs as caused by the FGF4 insertion on chromosome 12 and it has no additional predisposition to developing IVDD type 1. It cannot therefore pass this on to its offspring.
n/CDDY = short legs, increased risk of IVDD
The dog has one copy of the mutation. It has shortened legs and an increased susceptibility to IVDD type 1. The mutation is passed on to 50% of the offspring.
CDDY/CDDY = short legs, increased risk of IVDD
The dog has short legs and an increased risk of developing IVDD. The mutation is passed on to 100% of the offspring.
Recommendations for breeding
When mating two affected animals (n/CDDY or CDDY/CDDY), there is a chance that each puppy will inherit one or two copies of the mutation (n/CDDY or CDDY/CDDY) and thus an increased risk of developing IVDD. This should be taken into account when planning to breed animals. Animals with symptoms should be excluded from breeding.
Literature
Embersics C, Bannasch D, Batcher K, et al. Association of the FGF4L2 retrogene with fibrocartilaginous embolic myelopathy in dogs. J Vet Intern Med. 2024; 38(1): 258-267. doi:10.1111/jvim.16925
Bianchi CA, Marcellin-Little DJ, Dickinson PJ, Garcia TC, Li CF, Batcher K, Bannasch DL. FGF4L2 retrogene copy number is associated with intervertebral disc calcification and vertebral geometry in Nova Scotia Duck Tolling Retrievers. Am J Vet Res. 2023 Jan 26;84(3):ajvr.22.09.0167. doi: 10.2460/ajvr.22.09.0167. PMID: 36662606.
Bruun, C.S., Bruun, C., Marx, T., Proschowsky, H.F., Fredholm, M.: Breeding schemes for intervertebral disc disease in dachshunds: Is disc calcification score preferable to genotyping of the FGF4 retrogene insertion on CFA12? Canine Med Genet 7:18, 2020. Pubmed reference: 33292664. DOI: 10.1186/s40575-020-00096-6.
Batcher, K.; Dickinson, P.; Giuffrida, M.; Sturges, B.; Vernau, K.; Knipe, M.; Rasouliha, S.H.; Drögemüller, C.; Leeb, T.; Maciejczyk, K.; et al. Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes 2019, 10, 435. https://doi.org/10.3390/genes10060435
Brown, E.A., Dickinson, P.J., Mansour, T., Sturges, B.K., Aguilar, M., Young, A.E., Korff, C., Lind, J., Ettinger, C.L., Varon, S., Pollard, R., Brown, C.T., Raudsepp, T., Bannasch, D.L.: FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proc Natl Acad Sci U S A 114:11476-11481, 2017. Pubmed reference: 29073074. DOI: 10.1073/pnas.1709082114.
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