Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 216550 (trait) , 607817 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Species-specific symbol: TNS

Molecular basis: Starting with a list of candidate genes based on comparative clinical signs in other species (especially humans), Shearman and Wilton (2011) used linkage analysis to eventually narrow the field down to the VPS13B gene. They "sequenced each of the 63 exons of VPS13B in affected and control dogs and found that the causative mutation in Border collies is a 4 bp deletion in exon 19 of the largest transcript that results in premature truncation of the protein."

Clinical features: Affected dogs present with fever, gastrointestinal signs, polyarthritis, joint effusion, and lameness and failure to thrive between 6 and 12 weeks of age and have a characteristic ‘ferret-like’ elongated face (Allen et al., 1996; Shearman & Wilton, 2011; Mizukami et al., 2012; Mason et al., 2014; Hegler et al., 2020). Proprioception and placing and hopping reflexes were markedly reduced, while skin reflex and deep pain sensations were normal (Mizukami et al., 2012). Decreased level of consciousness, astasia, and incontinence were also reported by Mizukami et al. (2012). Ill thrift and continued recurrent/chronic infections are hallmark features (Hegler et al., 2020). Dogs are commonly dying or being euthanised by one year of age (Wouda et al. 2010). [IT thanks DVM students Laura Sweeting and Tracy Yeung, who provided the basis of this contribution in April 2022]

Pathology: Hegler et al. (2020) and Mizukami et al. (2013) discuss trapped neutrophil syndrome as a condition characterised by retention of neutrophils in the bone marrow of Border Collies. Whilst understanding of pathophysiological mechanisms is incomplete, neutrophils are seen to move inadequately from their haemopoietic site in bone marrow, to peripheral circulation (Mizukami et al., 2012). The two major features are reduced circulating neutrophil numbers (peripheral neutropoenia) and intramedullary myeloid hyperplasia (Mason et al., 2014). Eosinophilia, monocytosis, hypercholesterolaemia and nRBC in circulation and non-regenerative anaemia are reported (Mizukami et al., 2013). Radiographs showed capsular joint swelling and heterogeneous metaphyseal radiolucencies in multiple joints and cytology revealed non-degenerate neutrophilic inflammation in multiple joints (Hegler et al., 2020). [IT thanks DVM students Laura Sweeting and Tracy Yeung, who provided the basis of this contribution in April 2022]

Prevalence: Mizukami et al. (2016) reported the frequency of the 4bp deletion allele as 0.059 in 500 Border collies in Japan.

Genetic testing: Having developed "a novel MAS-PCR assay targeting the VPS13B gene", Lerdkrai and Phungphosop (2023) demonstrated "for the first time that carriers of [the likely causal 4bp deletion (OMIA variant 478) for] TNS exist in Border Collies in Thailand". The authors also reported that their "assay is a reliable and cost-effective tool for diagnosing TNS based on VPS13B genotypes and is suitable for routine clinical practice."

Breed: Border Collie (Dog) (VBO_0200193).
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: