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Update on Border Collie glaucoma and goniodysgenesis project

Kim M Summers
These notes present a summary of the problem of goniodysgenesis in the Border Collie and the research we have been doing to try to find the genetic variant(s) responsible. Please note that I am not a veterinarian and this is my personal understanding of the condition. Also note that the material herein is copyright and must not be used or distributed in any way (including uploading to social media) or with any modifications without my permission.

Background

In humans and dogs eye diseases are common. These can be caused by mutation in a single gene, or variants with major or minor effect in a number of genes. Several dog breeds have a predisposition
to glaucoma and the gene involved is known for some of them, for example ADAMTS10 in the Beagle and Norwegian Elkhound and COL1A2 in the Basset Hound. The goal of our project was to discover the genetic basis (if any) for glaucoma in the Border Collie.
Glaucoma results from failure to drain the fluid at the front of the eye. The build up of fluid causes damage to the optic nerve and retina, which is called glaucoma. Failure to drain the fluid can be caused by a blockage of the drainage channels (open angle glaucoma) or of the drain which gives access to these channels (narrow or closed angle glaucoma). This is explained at http://www.vmcli.com/veterinary-articles-canine-glaucoma.html.
Glaucoma in the Border Collie is due to a closed or narrow angle. This results from a failure of the “drain” (called the drainage angle) to develop properly. Instead of having wide open access to the drainage channels, the gap may be filled with thick fibres or sheets of tissue and the space itself may be narrow. This is called goniodysgenesis and is detected by veterinary ophthalmologists by doing a gonioscopy.
Goniodysgenesis can result in complete closure of the drainage angle. In that case no fluid can drain and glaucoma will result. However, many dogs with severe goniodysgenesis do not go on to get glaucoma. The reason why some do is not clear; this may be genetic or it may be something in the dog’s environment that finally blocks the drain.
The problem of glaucoma and goniodysgenesis has apparently been increasing in the Border Collie breed over the last 20 years. This may be due to extensive use of a small number of popular sires who may have been carriers of genetic changes that lead to the problem. We can trace all cases of glaucoma on the goniodysgenesis database to three common ancestors who appear on both sides of all the pedigrees, generally through more than one lineage. This suggests that goniodysgenesis and glaucoma may be genetic. In some dog breeds goniodysgenesis gets worse as the dog gets older, so the risk of glaucoma increases progressively, but a small study in the Border Collie suggested that goniodysgenesis may be stable from birth. This would need to be repeated with a larger number of animals, and ideally following a number of dogs throughout life.
It could be possible that the condition is not genetic in the Border Collie, but arises for some other reason. However, since it is not found in all dog breeds, since it appears to be associated with certain Border Collie lineages and since there is evidence for a common ancestor, we started from the hypothesis that it is genetic in some form. Examination of the pedigrees showed that any mode of inheritance could be possible.
Recessive inheritance would mean that both parents would be carriers usually without signs of the condition, but if an offspring inherited the variant from both parents it would be affected. Two affected parents would always have affected offspring.
Dominant inheritance would mean that one parent carried the genetic variant and had a
50% chance of passing it to offspring who would also be affected. So you would always see parent to offspring transmission.
Polygenic inheritance would indicate that there are a number of genes that can be mutated in the condition, some of which may have a major effect. The condition would run in families but the patterns of inheritance would not be predictable.
The project initiated by Alan Wilton and carried on in Edinburgh after his death was to look at the genetic basis and try to find a genetic variant that was associated with goniodysgenesis and glaucoma in the Border Collie. This would allow the development of a DNA based test which could identify carriers, so that appropriate breeding strategies can be put in place.

Findings of the project

1. Pedigree structure is consistent with recessive inheritance of severe goniodysgenesis that may progress to glaucoma. Mild goniodysgenesis may be a different condition, or there may be more than one gene that is involved in determining whether the dog suffers from severe or mild goniodysgenesis.
2. All dogs with glaucoma have the same three ancestors on both sides of the pedigree, usually through more than one line. This is consistent with the recessive model. It is likely that the mutation causing severe goniodysgenesis arose in one of these ancestors, or in one of their ancestors.
3. There is a region of the Border Collie DNA that appears to be associated with severe
goniodysgenesis. The table shows the findings for this region for severe and unaffected dogs. Genotype BB is associated with severe goniodysgenesis and genotype AB indicates a carrier.

Genotype

Clinical status

AA

AB

BB

Glaucoma

0

0

9 (100%)

Severe goniodysgenesis

0

2 (14%)

12 (86%)

Unaffected

29 (48.5%)

29 (48.5%)

2 (3%)

Note that these numbers may change as we examine more samples.
4. This region is not associated with mild goniodysgenesis, since 80% of cases diagnosed as mild are AA or AB. However when the dog has been diagnosed with moderate goniodysgenesis or simply as “affected” there is a higher risk that it is BB (45% for moderate;
63% for “affected”).

Genotype

Clinical status

AA

AB

BB

Mild

5

3

2

Moderate

3

3

5

Affected, no grade

2

1

5

TOTALS

10

7

12

5. There is some uncertainty about the diagnosis. Under the earlier scheme which graded the condition of the drainage angle from 0 (unaffected) to 5 (severe), all cases which were graded as 4 or 5 are BB, but only some graded 3 are BB. Under the proposed new scheme we expect that cases graded 3, and some graded 2 would be BB, but there have not been enough tests to validate this. Where the diagnosis was given simply as “affected”, the level of severity is not known. 63% of dogs who were diagnosed as affected without grading are BB.

Summary

We believe the BB genotype correlates strongly with severe goniodysgenesis with the risk of glaucoma. However, we do not yet know what determines progression to glaucoma in dogs with BB genotype. The severe goniodygsgnesis behaves as a recessive condition, ie AB dogs are carriers and AA dogs are clear.
Dogs with low grade goniodysgenesis were generally AA or AB (ie not the high risk genotype). We do not know yet whether there are other genes that contribute to this lower grade goniodysgenesis.
It would be advisable not to mate BB dogs (or severely affected dogs or those with glaucoma) at all, and to avoid AB x AB matings.