Chondrodystrophy (CDDY and IVDD Risk) with or without Chondrodysplasia (CDPA)

Common Symptoms

This test evaluates two regions of the canine genome to identify a Mutation on canine Chromosome 12 associated with chondrodystrophy and intervertebral disc disease (CDDY and IVDD Risk) and a mutation on canine chromosome 18 associated with chondrodysplasia (CDPA).

Chondrodystrophy with Intervertebral Disc Disease Risk Factor (CDDY with IVDD):

Intervertebral disc disease (IVDD) is an inherited disease affecting many dog breeds. A severe form of IVDD is associated with a genetic mutation in the FGF4 gene on canine chromosome 12. This genetic mutation is also identified as one cause of the characteristic trait for short legs (chondrodystrophy) in some dog breeds. Dogs affected with IVDD have premature degeneration and calcification of the cartilage discs that connect the vertebrae and function as shock absorbers for the spine. In some cases, these degenerative changes result in cartilage weakness and subsequent herniation of the discs into the spinal cord, causing Hemorrhage and inflammation. Affected dogs present with a variety of neurological clinical signs including severe back pain, abnormal gait, loss of balance, and limb weakness or paralysis, often requiring surgical intervention. Affected dogs are at risk of experiencing disc herniations at multiple sites along their spine during their lifetime. Therefore, it is common for dogs which have been surgically treated for disc herniation to experience a herniation in another location of the spine later in life.

Chondrodysplasia (CDPA):

Leg length is one of the traits that varies significantly among dog breeds. The characteristic short-legged trait of some breeds is referred to as chondrodysplasia (CDPA) but is also known as short-limbed or disproportional dwarfism. The trait is found in many breeds including the Dachshund, Pekingese, Corgi, and Basset Hound. Chondrodysplasia is inherited in an Autosomal Dominant manner and is associated with an insertion of a duplicate copy of the FGF4 gene (known as a retrogene insertion) on chromosome 18. It is thought that this mutation causes premature activation of other growth factor receptors leading to early calcification of the long bones resulting in limbs with a short and curved appearance. Although many breeds of dog with short legs carry two copies of the mutation, some carry only one or none, suggesting that there are other genetic factors responsible for short legs in other breeds including the mutation on canine chromosome 12 associated with chondrodystrophy and intervertebral disc disease risk (CDDY with IVDD).

Breed-Specific Information for the Havanese

The CFA18 FGF4 Mutation associated with chondrodysplasia (CDPA) has been identified in the Havanese. Approximately 5% out of 285 randomly selected Havanese tested had one copy of the mutation and 95% had two copies.

Testing Tips

Two genetic mutations are associated with shortened legs in dogs. Both mutations consist of copied sections (duplication) of the canine FGF4 gene (called an FGF4-retrogene) that have been inserted into two aberrant locations in the genome; one in Chromosome 12 (CFA12 FGF4; associated with CDDY and IVDD risk) and one in chromosome 18 (CFA18 FGF4; associated with chondrodysplasia [CDPA], but not associated with IVDD). Appropriate breeding decisions regarding dogs which have inherited the CFA12 FGF4 Mutation (WT/M or M/M) need to address both the potential loss of genetic diversity in a population which would occur if dogs with this mutation were prohibited from breeding as well as the loss of the short-legged appearance that is a defining physical characteristic for some breeds. In breeds which inherit both mutations, breeders may use genetic testing results to selectively breed for the CDPA (CFA18 FGF4) mutation while breeding away from the CDDY and IVDD risk (CFA12 FGF4) mutation to reduce IVDD risk and retain the short-legged appearance. However, the frequency of each mutation varies between breeds and, in some cases, may not be conducive to such a breeding strategy. For example, breeds with extreme limb shortening (e.g. Basset hound, Dachshund, Corgi) typically develop their appearance due to inheritance of both the CFA12 FGF4 and CFA18 FGF4 mutations. In addition, depending on the breed, offspring born without either the CFA12 FGF4 or CFA18 FGF4 mutations may display longer limbs than cohorts and, therefore, not meet specific breed standards. Genetic testing for the presence of the two FGF4 retrogene insertions in canine chromosome 12 and 18 will reliably determine whether a dog is a genetic Carrier of the mutation associated with IVDD and chondrodystrophy (CDDY) and/or the mutation associated with chondrodysplasia (CDPA).

Chondrodystrophy with Intervertebral Disc Disease Risk Factor (CDDY with IVDD):

Intervertebral disc disease associated with the CFA12 FGF4 mutation is inherited in an Autosomal Dominant manner meaning that a dog only needs to inherit one copy of the mutated gene to be at an increased risk of developing the disease. Each pup that is born to an affected dog has at least a 50% chance of inheriting one copy of the CFA12 FGF4 gene mutation. Reliable genetic testing is important for determining breeding practices. Because symptoms of IVDD do not appear until adulthood and because the mutation shows Incomplete Penetrance, genetic testing should be performed before breeding. In order to eliminate this mutation from breeding lines and to avoid the potential of producing affected pups, breeding of dogs known to have the mutation is not recommended. However, nearly 100% of the dogs in some short-legged breeds have two copies of this mutation (e.g. dachshund), making it virtually impossible to breed away from this mutation in these breeds. Dogs that are not carriers of the mutation have no increased risk of having IVDD-affected pups due to this mutation. Shortened limbs associated with the CFA12 FGF4 mutation are inherited in a semi-dominant manner meaning that dogs with a single copy of the mutation display an intermediate leg length between the normal length legs of dogs that do not inherit the mutation and dogs with two copies of the mutation which display the shortest leg length associated with this mutation.

Chondrodysplasia (CDPA):

Chondrodysplasia associated with the CFA18 FGF4 mutation is inherited in an autosomal dominant manner meaning that dogs that inherit one or two copies of the CFA18 FGF4 mutation are likely to have short legs. However, the actual leg length of the dog is a result of a combination of factors including variants in other genes. The chondrodysplasia (CDPA) mutation is also referred to as the CD Locus with the normal, wild type (WT) Allele referred to as the recessive “cd” allele and the mutant (M) allele referred to as the dominant “CD” allele. Thus, a dog that carries one copy of the CFA18 FGF4 mutation (WT/M or cd/CD) will likely have shortened legs and will pass the CFA18 FGF4 mutation to 50% of its offspring. A dog that carries two copies of the CFA18 FGF4 mutation (M/M or CD/CD) will pass one copy to 100% of its offspring. A dog with no copies of the CFA18 FGF4 mutation (WT/WT or cd/cd) will pass one copy of the WT or cd allele to 100% of its offspring.

There may be other causes of this condition in dogs and a normal result does not exclude a different mutation in this gene or any other gene that may result in a similar genetic disease or trait.

References

• Bannasch D, Batcher K, Leuthard F, Bannasch M, Hug P, Marcellin-Little DJ, Dickinson PJ, Drögemüller M, Drögemüller C, Leeb T. The Effects of FGF4 Retrogenes on Canine Morphology. Genes (Basel). 2022 Feb 10;13(2):325. [PubMed: 35205370]
• Batcher K, Dickinson P, Giuffrida M, Sturges B, Vernau K, Knipe M, Rasouliha SH, Drogemuller C, Leeb T, Maciejczyk K, Jenkins CA, Mellersh C, Bannasch D. Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes (Basel). 2019 Jun 7;10(6). pii: E435. doi: 10.3390/genes10060435. [PubMed: 31181696]
• Bellamy KKL, Lingaas F. Short and sweet: foreleg abnormalities in Havanese and the role of the FGF4 retrogene. Canine Med Genet. 2020 Dec 7;7(1):19. doi: 10.1186/s40575-020-00097-5. [PubMed: 33372642]
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• Dickinson PJ, Bannasch DL. Current Understanding of the Genetics of Intervertebral Disc Degeneration. Front Vet Sci. 2020 Jul 24;7:431. doi: 10.3389/fvets.2020.00431. eCollection 2020. [PubMed: 32793650]
• Fenn J, Olby NJ, and Canine Spinal Cord Injury Consortium (CANSORT-SCI). Classification of Intervertebral Disc Disease. Front Vet Sci. 2020 Oct 6;7:579025. doi: 10.3389/fvets.2020.579025. eCollection 2020. [PubMed: 33134360]
• Parker HG, VonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA. An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science. 2009 Aug 21;325(5943):995-8. [PubMed: 19608863]