OMIA 002301-9615 : Laryngeal paralysis and polyneuropathy, CNTNAP1 related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 618186 , 602346

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.

Associated gene:

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

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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Labrador Retriever Leonberger Saint Bernard Laryngeal paralysis and polyneuropathy CNTNAP1 LPPN3 missense CanFam3.1 9 g.20298261C>T c.2810G>A p.Gly937Glu XM_548083.6:c.2810G>A; XP_548083.3:p.Gly937Glu 2020 33261176

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.
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 <i>CNTNAP1</i> missense variant is associated with canine laryngeal paralysis and polyneuropathy. Genes (Basel) 11:, 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.

Edit History


  • Created by Frank Nicholas on 10 Dec 2020
  • Changed by Imke Tammen2 on 10 Dec 2020
  • Changed by Imke Tammen2 on 11 Dec 2020