OMIA:002301-9615 : Laryngeal paralysis and polyneuropathy, CNTNAP1-related in Canis lupus familiaris
Categories: Nervous system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 618186 (trait) , 602346 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2020
History: Letko et al. (2020): “Various mostly breed-specific canine inherited neuropathies form a heterogeneous group of degenerative diseases affecting motor and/or sensory and autonomic peripheral nerves. This group includes mixed forms of LP and PN [Granger, 2011], i.e., the laryngeal paralysis and polyneuropathy complex (LPPN), which has variable ages of onset among and across several dog breeds.”
Letko et al. (2020) "identified a potentially causative genetic variant in CNTNAP1 associated with autosomal recessive younger-onset LPPN in large and giant dogs, specifically Leonbergers, Saint Bernards, and Labrador retrievers.”
Variants in other genes have been associated with other forms of polyneuropathy and/or laryngeal paralysis in various breeds: OMIA 001917-9615 (ARHGEF10), OMIA 002119-9615 (GJA9), OMIA 001970-9615 (RAB3GAP1), OMIA 002284-9615 (SBF2), OMIA 002222-9615 (RAPGEF6). References relating to polyneuropathies and laryngeal paralysis in dogs without known genetic associations are listed under OMIA 001292-9615 and OMIA 001206-9615, respectively.
Molecular basis: Letko et al. (2020): "Using across-breed genome-wide association, haplotype analysis, and whole-genome sequencing, we identified a missense variant in the CNTNAP1 gene (c.2810G>A; p.Gly937Glu) in which homozygotes in both studied breeds are affected. ...
Homozygosity for the missense variant in the CNTNAP1 gene is significantly associated with the development of LPPN in large and giant-sized dogs, indicating recessive inheritance in all three studied breeds … Homozygotes for the missense allele in breeds other than the Leonberger, Saint Bernard, and Labrador retriever were identified in 46 English bulldogs, six Irish terriers, two boxers, one bullmastiff, one Peruvian hairless dog, one Yorkshire terrier, and one golden retriever… , all with unknown precise health history. .... The impact of this variant on health in English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies, remains unclear."
Clinical features: Letko et al. (2020): "key feature across breeds being breathing difficulty, often described as noisy or raspy breathing ... . Additional clinical signs, which were noted variably among the dogs, included difficulty swallowing, changes in barking frequency and quality, high-stepping and uncoordinated gait, stumbling and tripping, exercise intolerance, and limb muscle atrophy."
Pathology: Letko et al. (2020): "Peroneal nerve biopsies were evaluated .... Compared to control nerve, pathological changes were similar among affected dogs of all three breeds and included a subjective decrease in the number of myelinated nerve fibers compared to control nerve ... with scattered inappropriately thin myelin sheaths for the axon diameter ..."
Breeds: Labrador, Leonberger, Saint Bernard.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|CNTNAP1||contactin associated protein 1||Canis lupus familiaris||9||NC_051813.1 (21026834..21012211)||CNTNAP1||Homologene, Ensembl , NCBI gene|
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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|
|1273||Labrador Retriever Leonberger Saint Bernard||Laryngeal paralysis and polyneuropathy||CNTNAP1||LPPN3||missense||Naturally occurring variant||CanFam3.1||9||g.20298261C>T||c.2810G>A||p.(G937E)||XM_548083.6:c.2810G>A; XP_548083.3:p.Gly937Glu||rs24587752||rs24587752||2020||33261176|
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.
|2020||Letko, A., Minor, K.M., Friedenberg, S.G., Shelton, G.D., Salvador, J.P., Mandigers, P.J.J., Leegwater, P.A.J., Winkler, P.A., Petersen-Jones, S.M., Stanley, B.J., Ekenstedt, K.J., Johnson, G.S., Hansen, L., Jagannathan, V., Mickelson, J.R., Drögemüller, C. :|
|A CNTNAP1 missense variant is associated with canine laryngeal paralysis and polyneuropathy. Genes (Basel) 11:1426, 2020. Pubmed reference: 33261176 . DOI: 10.3390/genes11121426.|
|2011||Granger, N. :|
|Canine inherited motor and sensory neuropathies: an updated classification in 22 breeds and comparison to Charcot-Marie-Tooth disease. Vet J 188:274-85, 2011. Pubmed reference: 20638305 . DOI: 10.1016/j.tvjl.2010.06.003.|
- Changed by Imke Tammen2 on 10 Dec 2020
- Created by Frank Nicholas on 10 Dec 2020
- Changed by Imke Tammen2 on 11 Dec 2020