Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 618186 (trait) , 602346 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 Retriever (Dog) (VBO_0200800), Leonberger (Dog) (VBO_0200819), Pyrenean Shepherd (Dog) (VBO_0201117), Saint Bernard (Dog) (VBO_0201160).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: