Test Detail

Expanded genetic panel for the border collie combining eight hereditary conditions: Raine syndrome (dental hypomineralization due to FAM20C), collie eye anomaly (CEA, choroidal hypoplasia and possible colobomas), glaucoma and goniodysgenesis (GG, iridocorneal angle abnormality with risk of closed-angle glaucoma), neuronal ceroid lipofuscinosis (NCL due to CLN5), ivermectin sensitivity (MDR1), Imerslund-Gräsbeck syndrome (IGS, selective cobalamin malabsorption with megaloblastic anaemia), trapped neutrophil syndrome (TNS, neutropenia with storage) and hereditary sensory neuropathy (SN, degeneration of sensory neurons with autoamputation).

Border collie. NCL due to CLN5 has an estimated allele frequency of around 3.5% in Australia and ~4% in Japan. CEA due to NHEJ1 has variable frequencies (some estimates of 30% carriers). IGS due to CUBN and SN due to FAM134B are infrequent but are screened due to their severity. Glaucoma/GG due to OLFML3 has been described with an allele frequency of ~4.4% in border collies in the United Kingdom. For Raine and TNS, population frequencies are not reliably published.

- Raine: severe dental hypomineralization, fragile and brownish teeth with premature wear and pulpitis
- CEA: choroidal hypoplasia (pale patch in the fundus), possible peripapillary colobomas and, in severe cases, retinal detachment and blindness
- GG: goniodysgenesis (pectinate ligament abnormality), risk of acute closed-angle glaucoma
- NCL: onset at 18-24 months with behavioural changes, hyperactivity, ataxia, blindness, seizures
- MDR1: neurotoxicity from ivermectin, moxidectin, loperamide
- IGS: megaloblastic anaemia, lethargy, growth retardation, neutropenia, neurological signs due to B12 deficiency
- TNS: chronic neutropenia, recurrent infections, growth retardation
- SN: proprioceptive ataxia, loss of pain sensation, autoamputation of limbs, onset between 2-7 months

Raine syndrome in the border collie was associated with a missense variant in FAM20C (c.899C>T, p.A300V) by Hytönen and colleagues (2016, PLoS Genetics). CEA was associated with a 7.8 kb intronic deletion in NHEJ1 by Parker and colleagues (2007), shared among herding breeds through a founder effect. Glaucoma/goniodysgenesis in the border collie was associated with a missense variant in OLFML3 (c.590G>A, p.R197Q) by Pugh and colleagues (2019, G3). NCL in the border collie was attributed to a nonsense mutation in CLN5 (c.619C>T, p.Q206X) by Melville and colleagues (2005, Genomics). IGS in the border collie was associated with a frameshift deletion in CUBN (c.8392delC) by Owczarek-Lipska and colleagues (2013, PLoS ONE) and Fyfe et al. (2013). TNS is associated with a variant in VPS13B, characterized by the groups of Wilton and Bhatt. SN in the border collie was associated with an inversion disrupting FAM134B (RETREG1) by Forman and colleagues (2016, G3). MDR1 is the classic ABCB1 deletion.

- Genotype breeding animals for FAM20C, NHEJ1, OLFML3, CLN5, ABCB1, CUBN, VPS13B and FAM134B before mating
- Do not mate two carriers for the same variant
- A carrier can be mated with a clear animal and the offspring intended for breeding must be tested
- For OLFML3: the test is not absolute (incomplete penetrance); complement with gonioscopy
- For homozygous MDR1: avoid ivermectin, moxidectin, loperamide and other P-gp substrates; warn the veterinarian
- After a confirmed case, do not repeat the parental mating and communicate the status to the buyer
- For Raine, consider early dental management in homozygous puppies (extraction/capping of affected teeth)

CEA due to NHEJ1 can show « go normal » (homozygous dogs that pass as normal on examination at the appropriate age). Glaucoma in the border collie requires gonioscopy in addition to the genetic test (the association with OLFML3 is strong but not exclusive). NCL must be distinguished from other neurodegenerative conditions. IGS is treated with parenteral cyanocobalamin supplements. SN has a poor prognosis and must be distinguished from acral mutilation syndrome (AMS) of the German Shorthaired Pointer. Raine involves intensive and costly dental management.

1. Hytönen MK et al. (2016) Molecular characterization of three canine models of human rare bone diseases: Caffey, van den Ende-Gupta, and Raine syndromes. PLoS Genet 12:e1006037. PMID: 27187611
2. Parker HG et al. (2007) Breed relationships facilitate fine-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds. Genome Res 17:1562-71. PMID: 17916641
3. Pugh CA et al. (2019) Arginine to glutamine variant in olfactomedin like 3 (OLFML3) is a candidate for severe goniodysgenesis and glaucoma in the Border Collie dog breed. G3 (Bethesda) 9:943-54. PMID: 30696701
4. Melville SE et al. (2005) A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics 86:287-94. PMID: 16033706
5. Owczarek-Lipska M et al. (2013) A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome. PLoS One 8:e61144. PMID: 23613799
6. Forman OP et al. (2016) An inversion disrupting FAM134B is associated with sensory neuropathy in the Border Collie dog breed. G3 (Bethesda) 6:2687-92. PMID: 27527794