Categories: Respiratory system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 610499 (gene)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

History: 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 002301-9615 (CNTNAP1). References relating to polyneuropathies and laryngeal paralysis in dogs without known genetic associations are listed under OMIA 001292-9615 and OMIA 001206-9615, respectively.

Mapping: "Using a genome-wide association study and haplotype analyses, . . . [Hadji Rasouliha et al. (2019)] mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11."

Markers: Hadji Rasouliha et al. (2019) identified "a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36) . . . a major genetic risk factor [for this disorder, laryngeal paralysis (LP), in Miniature Bull Terriers] involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP". The authors also reported that "The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame." Hadji Rasouliha et al. (2019) quantified the effect of the marker by calculating relative risk in a cohort of "all Miniature Bull Terriers fulfilling the inclusion criteria (n = 243). In this cohort, homozygosity for the RAPGEF6 insertion was associated with a 9.91-fold (95% CI: 5.75–17.1, p < 0.0001) increased risk for LP compared with dogs, which were homozygous wildtype or carried the insertion allele in heterozygous state. The risk in dogs carrying the insertion in heterozygous state was not significantly increased compared to dogs homozygous for the wildtype allele (RR = 1.75, 95% CI: 0.61–5.03, p = 0.30)".

Clinical features: Hadji Rasouliha et al. (2019): "Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies."

Prevalence: Hadji Rasouliha et al. (2019): " The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds".

Breed: Miniature Bull Terrier (Dog) (VBO_0200882).
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: