OMIA 000157-9615 : Intervertebral disc disease, type I in Canis lupus familiaris

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: 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, Basset Hound, Beagle, Cardigan Welsh Corgi, Cavalier King Charles Spaniel, Chesapeake Bay Retriever, Chihuahua, Coton de Tulear, Dachshund, English Springer Spaniel, French Bulldog, Miniature Poodle, Nova Scotia Duck Tolling retriever, Pekingese, Shih-Tzu, Toy Poodle.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
FGF4 retrogene in CFA12 Canis lupus familiaris - no genomic information (-..-) FGF4 retrogene in CFA12 Ensembl

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
855 American Cocker Spaniel Basset Hound Beagle Cardigan Welsh Corgi Chesapeake Bay Retriever Chihuahua Coton de Tulear Dachshund English Springer Spaniel French Bulldog Nova Scotia Duck Tolling retriever Intervertebral disc disease, type I FGF4 retrogene in CFA12 FGF4L2 insertion, gross (>20) Naturally occurring variant CanFam3.1 12 " 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) . . . ." 200922: g. info moved here (g.33710178_33710179insMF040221) until it can be standardised 2017 29073074

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2022 Bannasch, D., Batcher, K., Leuthard, F., Bannasch, M., Hug, P., Marcellin-Little, D.J., Dickinson, P.J., Drögemüller, M., Drögemüller, C., Leeb, T. :
The effects of FGF4 retrogenes on canine morphology. Genes (Basel) 13:325, 2022. Pubmed reference: 35205370. DOI: 10.3390/genes13020325.
Lee, S., Hwang, J., Ko, J., Jeong, J., Eom, K., Kim, J. :
Comparison between T2-weighted two-dimensional and three-dimensional fast spin-echo MRI sequences for characterizing thoracolumbar intervertebral disc disease in small-breed dogs. Vet Radiol Ultrasound 63:216-223, 2022. Pubmed reference: 35023239. DOI: 10.1111/vru.13049.
2021 Horvatić, A., Gelemanović, A., Pirkić, B., Smolec, O., Beer Ljubić, B., Rubić, I., Eckersall, P.D., Mrljak, V., McLaughlin, M., Samardžija, M., Lipar, M. :
Multi-omics approach to elucidate cerebrospinal fluid changes in dogs with intervertebral disc herniation. Int J Mol Sci 22:11678, 2021. Pubmed reference: 34769107. DOI: 10.3390/ijms222111678.
2020 Batcher, K., Dickinson, P., Maciejczyk, K., Brzeski, K., Rasouliha, S.H., Letko, A., Drögemüller, C., Leeb, T., Bannasch, D. :
Multiple FGF4 retrocopies recently derived within canids. Genes (Basel) 11:839, 2020. Pubmed reference: 32717834. DOI: 10.3390/genes11080839.
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.
da Costa, R.C., De Decker, S., Lewis, M.J., Volk, H. :
Diagnostic imaging in intervertebral disc disease. Front Vet Sci 7:588338, 2020. Pubmed reference: 33195623. DOI: 10.3389/fvets.2020.588338.
Fenn, J., Olby, N.J. :
Classification of intervertebral disc disease. Front Vet Sci 7:579025, 2020. Pubmed reference: 33134360. DOI: 10.3389/fvets.2020.579025.
Spitzbarth, I., Moore, S.A., Stein, V.M., Levine, J.M., Kühl, B., Gerhauser, I., Baumgärtner, W. :
Current insights into the pathology of canine intervertebral disc extrusion-induced spinal cord injury. Front Vet Sci 7:595796, 2020. Pubmed reference: 33195632. DOI: 10.3389/fvets.2020.595796.
2019 Batcher, K., Dickinson, P., Giuffrida, M., Sturges, B., Vernau, K., Knipe, M., Rasouliha, S.H., Drögemüller, C., Leeb, T., Maciejczyk, K., Jenkins, C.A., Mellersh, C., Bannasch, D. :
Phenotypic effects of FGF4 retrogenes on intervertebral disc disease in dogs. Genes (Basel) 10:435, 2019. Pubmed reference: 31181696. DOI: 10.3390/genes10060435.
Murphy, B.G., Dickinson, P., Marcellin-Little, D.J., Batcher, K., Raverty, S., Bannasch, D. :
Pathologic features of the intervertebral disc in young Nova Scotia Duck Tolling Retrievers confirms chondrodystrophy degenerative phenotype associated with genotype. Vet Pathol :300985819868731, 2019. Pubmed reference: 31526126. DOI: 10.1177/0300985819868731.
Wyatt, S.E., Lafuente, P., Ter Haar, G., Packer, R.M.A., Smith, H., De Decker, S. :
Gait analysis in French bulldogs with and without vertebral kyphosis. Vet J 244:45-50, 2019. Pubmed reference: 30825894. DOI: 10.1016/j.tvjl.2018.12.008.
2017 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.
2016 Dugat, D.R., Bartels, K.E., Payton, M.E. :
Recurrence of disk herniation following percutaneous laser disk ablation in dogs with a history of thoracolumbar intervertebral disk herniation: 303 cases (1994-2011). J Am Vet Med Assoc 249:1393-1400, 2016. Pubmed reference: 27901458. DOI: 10.2460/javma.249.12.1393.
Packer, R.M., Seath, I.J., O'Neill, D.G., De Decker, S., Volk, H.A. :
DachsLife 2015: an investigation of lifestyle associations with the risk of intervertebral disc disease in Dachshunds. Canine Genet Epidemiol 3:8, 2016. Pubmed reference: 27826450. DOI: 10.1186/s40575-016-0039-8.
Shi, Z.Y., Gu, T., Zhang, C., Wang, D.L., He, Q., Ruan, D.K. :
Computed tomography-guided nucleus pulposus biopsy for canine intervertebral disc degeneration preparation: a radiology and histology study. Spine J 16:252-8, 2016. Pubmed reference: 24845965. DOI: 10.1016/j.spinee.2013.11.061.
2015 Hakozaki, T., Iwata, M., Kanno, N., Harada, Y., Yogo, T., Tagawa, M., Hara, Y. :
Cervical intervertebral disk herniation in chondrodystrophoid and nonchondrodystrophoid small-breed dogs: 187 cases (1993-2013). J Am Vet Med Assoc 247:1408-11, 2015. Pubmed reference: 26642135. DOI: 10.2460/javma.247.12.1408.
Lappalainen, A.K., Mäki, K., Laitinen-Vapaavuori, O. :
Estimate of heritability and genetic trend of intervertebral disc calcification in Dachshunds in Finland. Acta Vet Scand 57:78, 2015. Pubmed reference: 26597811. DOI: 10.1186/s13028-015-0170-7.
Oberbauer, A.M., Belanger, J.M., Bellumori, T., Bannasch, D.L., Famula, T.R. :
Ten inherited disorders in purebred dogs by functional breed groupings. Canine Genet Epidemiol 2:9, 2015. Pubmed reference: 26401337. DOI: 10.1186/s40575-015-0021-x.
Rosenblatt, A.J., Hill, P.B., Davies, S.E., Webster, N.S., Lappalainen, A.K., Bottema, C.D., Caraguel, C.G. :
Precision of spinal radiographs as a screening test for intervertebral disc calcification in Dachshunds. Prev Vet Med 122:164-73, 2015. Pubmed reference: 26493589. DOI: 10.1016/j.prevetmed.2015.09.015.
2014 Lappalainen, A.K., Vaittinen, E., Junnila, J., Laitinen-Vapaavuori, O. :
Intervertebral disc disease in Dachshunds radiographically screened for intervertebral disc calcifications. Acta Vet Scand 56:89, 2014. Pubmed reference: 25523328. DOI: 10.1186/s13028-014-0089-4.
Rosenblatt, A.J., Bottema, C.D., Hill, P.B. :
Radiographic scoring for intervertebral disc calcification in the Dachshund. Vet J 200:355-361, 2014. Pubmed reference: 24742872. DOI: 10.1016/j.tvjl.2014.03.023.
2013 Bellumori, T.P., Famula, T.R., Bannasch, D.L., Belanger, J.M., Oberbauer, A.M. :
Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995-2010). J Am Vet Med Assoc 242:1549-55, 2013. Pubmed reference: 23683021. DOI: 10.2460/javma.242.11.1549.
Bergknut, N., Smolders, L.A., Grinwis, G.C., Hagman, R., Lagerstedt, A.S., Hazewinkel, H.A., Tryfonidou, M.A., Meij, B.P. :
Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc and characteristics of intervertebral disc degeneration. Vet J 195:282-291, 2013. Pubmed reference: 23177522. DOI: 10.1016/j.tvjl.2012.10.024.
Bergknut, N., Meij, B.P., Hagman, R., de Nies, K.S., Rutges, J.P., Smolders, L.A., Creemers, L.B., Lagerstedt, A.S., Hazewinkel, H.A., Grinwis, G.C. :
Intervertebral disc disease in dogs - Part 1: A new histological grading scheme for classification of intervertebral disc degeneration in dogs. Vet J 195:156-163, 2013. Pubmed reference: 22789628. DOI: 10.1016/j.tvjl.2012.05.027.
Jeffery, N.D., Levine, J.M., Olby, N.J., Stein, V.M. :
Intervertebral disk degeneration in dogs: Consequences, diagnosis, treatment, and future directions. J Vet Intern Med 27:1318-1333, 2013. Pubmed reference: 24010573. DOI: 10.1111/jvim.12183.
Kranenburg, H.J., Grinwis, G.C., Bergknut, N., Gahrmann, N., Voorhout, G., Hazewinkel, H.A., Meij, B.P. :
Intervertebral disc disease in dogs - Part 2: Comparison of clinical, magnetic resonance imaging, and histological findings in 74 surgically treated dogs. Vet J 195:164-171, 2013. Pubmed reference: 22795604. DOI: 10.1016/j.tvjl.2012.06.001.
Smolders, L.A., Bergknut, N., Grinwis, G.C., Hagman, R., Lagerstedt, A.S., Hazewinkel, H.A., Tryfonidou, M.A., Meij, B.P. :
Intervertebral disc degeneration in the dog. Part 2: Chondrodystrophic and non-chondrodystrophic breeds. Vet J 195:292-299, 2013. Pubmed reference: 23154070. DOI: 10.1016/j.tvjl.2012.10.011.
2012 Mogensen, M.S., Scheibye-Alsing, K., Karlskov-Mortensen, P., Proschowsky, H.F., Jensen, V.F., Bak, M., Tommerup, N., Kadarmideen, H.N., Fredholm, M. :
Validation of genome-wide intervertebral disk calcification associations in dachshund and further investigation of the chromosome 12 susceptibility locus. Front Genet 3:225, 2012. Pubmed reference: 23125846. DOI: 10.3389/fgene.2012.00225.
Nagano, S., Fujiki, M., Tokunaga, S., Misumi, K. :
Analysis of cartilage oligomeric matrix protein and matrix metalloproteinase-9 in cerebrospinal fluid of miniature dachshund with intervertebral disc herniation. Res Vet Sci 93:1487-92, 2012. Pubmed reference: 22440362. DOI: 10.1016/j.rvsc.2012.02.014.
2011 Mogensen, M.S., Karlskov-Mortensen, P., Proschowsky, H.F., Lingaas, F., Lappalainen, A., Lohi, H., Jensen, V.F., Fredholm, M. :
Genome-wide association study in dachshund: identification of a major locus affecting intervertebral disc calcification. J Hered :S81-6, 2011. Pubmed reference: 21846751. DOI: 10.1093/jhered/esr021.
2001 Jensen, V.F. :
Asymptomatic radiographic disappearance of calcified intervertebral disc material in the Dachshund. Vet Radiol Ultrasound 42:141-8, 2001. Pubmed reference: 11327362.
2000 Jensen, V.F., Ersbøll, A.K. :
Mechanical factors affecting the occurrence of intervertebral disc calcification in the dachshund--a population study. J Vet Med A Physiol Pathol Clin Med 47:283-96, 2000. Pubmed reference: 10932525.
Jensen, V.F., Christensen, K.A. :
Inheritance of disc calcification in the dachshund. J Vet Med A Physiol Pathol Clin Med 47:331-40, 2000. Pubmed reference: 11008442.
1975 Braund, K.G., Ghosh, P., Taylor, T.K.F., Larsen, L.H. :
Morphological studies of the canine intervertebral disc: the assignment of the Beagle to the achondroplastic classification Research in Veterinary Science 19:167-172, 1975. Pubmed reference: 1166121.
1952 Hansen, H.J. :
A pathologic-anatomical study on disc degeneration in dog, with special reference to the so-called enchondrosis intervertebralis. Acta Orthop Scand Suppl 11:1-117, 1952. Pubmed reference: 14923291.
1951 Hansen, H.J. :
A pathologic-anatomical interpretation of disc degeneration in dogs. Acta Orthop Scand 20:280-93, 1951. Pubmed reference: 14894198.

Edit History


  • Created by Frank Nicholas on 06 Sep 2005
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