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Chondrodystrophy (CDDY) & Intervertebral Disc Disease (IVDD) [RESEARCH ONLY]

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Description:

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).

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.

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).

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 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.

Want to understand more about IVDD? Click here for a Fact Sheet.

Test Overview:

Chondrodystrophy in dogs is defined by dysplastic, shortened long bones and premature degeneration and calcification of intervertebral discs. This disease is therefore much more common in the chondrodystrophic breeds (that is short-legged breeds such as the dachshund, basset hound and corgi) and the dachshund accounts for 45 - 70% of all intervertebral disc disease (IVDD) in dogs. Chondrodystrophic breeds are prone to a type of disc degeneration called chondroid metaplasia, where the intervertebral discs in the spinal column become dried out, hardened and calcified at an early age. The discs are then less able to flex with movement, and more prone to bulging or rupture. The calcified inner disc material puts pressure on the spinal cord, causing pain and damage to the nerves running through the spinal cord. Severe pain to paralysis can occur, as well as inability to urinate or defaecate, and disc ruptures in the neck can cause respiratory paralysis and death. Signs of intervertebral disc rupture most commonly occur in chondrodystrophic breeds between 3-6 years of age. Calcification of discs is generally apparent on x-rays by 2 years. Ruptures can occur anywhere, but are more common in the upper back (65%), followed by the neck area (18%). IVDD can occur in non-chondrodystrophic breeds as well, with the most commonly affected being German shepherd dogs, Labrador retrievers and Dobermanns. In these breeds disc rupture tends to occur later, at around 8 years of age on average. Obesity is also a major risk factor for IVDD. Disc rupture is generally suspected from clinical signs of severe pain or neurologic deficits, and is confirmed via myelography (injecting dye into the spinal canal which is then visible on x-ray) or MRI. Plain x-rays are not diagnostic for disc rupture, however they may rule out other conditions. In less severe cases treatment may be successful with medication, nursing and strict cage rest for a number of weeks. With significant nerve deficits or any ongoing deterioration, surgical removal of the prolapsed disc is the treatment of choice. Recovery from surgery involves physiotherapy and good pain management, and if treated early the prognosis for IVDD is generally good.

Category:

Musculoskeletal - Associated with muscles, bones and associated structures

Gene:

CFA12 FGF4, CFA18 FGF4

Variant Detected:

chr12:33710168-33710178 (canFam3): 3209 bp insertion with duplication (AAGTCAGACAGAG); chr18:20443725-20443726 (canFam3): ~5 kb insertion; chr18:48415661 (canFam3): G/A

Severity:

Low-Moderate. This disease can cause some discomfort and/or dysfunction in the affected animal. It does not generally affect life expectancy.

Mode of Inheritance:

Autosomal Dominant with Incomplete Penetrance

Research Citation(s):

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] Brown EA, Dickinson PJ, Mansour T, Sturges BK, Aguilar M, Young AE, Korff C, Lind J, Ettinger CL, Varon S, Pollard R, Brown CT, Raudsepp T, Bannasch DL. FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11476-11481. doi: 10.1073/pnas.1709082114. [PubMed: 29073074] 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]

Associated Breed(s):

American Cocker Spaniel, Australian Cobberdog, Australian Labradoodle , Basset Hound, Beagle, Bichon Frise, Cardigan Welsh Corgi, Cavador, Cavalier King Charles Spaniel, Cavoodle, Chesapeake Bay Retriever , Chihuahua, Chinese Crested, Coton De Tulear, Dandie Dinmont Terrier, English Springer Spaniel, French Bulldog, Harlequin Pinscher, Havanese, Havanese Terrier Toy, Jack Russell Terrier, Labradoodle , Labradoodle Retrodoodle , Miniature American Shepherd, Miniature Australian Bulldog, Miniature Australian Shepherd, Miniature Fox Terrier, Miniature Pinscher , Miniature Poodle, Mixed Breed, Moodle, Nova Scotia Duck Tolling Retriever , Pekingese, Pembroke Welsh Corgi, Portuguese Water Dog, Scottish Terrier , Shih tzu, Spoodle, Toy Poodle,

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