Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611290 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2007

Cross-species summary: Phene was previously called 'Collie eye anomaly' [16/06/2023]

Species-specific name: Collie eye anomaly; Collie eye defect, choroidal hypoplasia, Collie ectasia syndrome, scleral ectasia syndrome

Species-specific symbol: cea

Species-specific description: Collie eye anomaly (CEA) is a complex developmental defect of the posterior segment of the eye characterized by choroid hypoplasia. Malformations are present at birth and may include inadequate development of the choroid (choroidal hypoplasia), defects of the choroid, sclera, and/or optic nerve (coloboma/staphyloma), and complete retinal detachment (with or without hemorrhage). Mildly affected animals will have no detectable vision deficit. (Genetics Committee of the American College of Veterinary Opthalmologists, 2021).

Inheritance: Colobomas only occur in dogs of four breeds (Collie, Border Collie, Australian Shepherd, and Shetland Sheepdog) that are homozygous for the likely causal mutation (Parker et al., 2007). Some affected dogs in these breeds have been observed to “go normal” later, most of which were homozygous for the likely causal mutation, but a small minority were heterozygous. This suggests other loci may have an effect on CEA expression, i.e. that the disorder is multifactorial.

Mapping: CFA37

Markers: Kucharczyk et al. (2019) reported "the occurrence of choroidal hypoplasia in the Australian Kelpie breed in Poland, the affected dogs testing positive for the Collie Eye Anomaly NHEJ1 gene mutation" (i.e. g.28697542-28705340del7799)

Molecular basis: By a neat bit of detective work that makes use of between-breed variation in linkage disequilibrium in tracking down mutations that are common to several breeds, Parker et al. (2007) discovered that a likely causal variant for Collie Eye Anomaly in four breeds (Collie, Border Collie, Australian Shepherd, and Shetland Sheepdog) is a deletion of 7.8kb in the NHEJ1 gene: 37:g.28,697,542–28,705,340del. A warning that the causality of this mutant may not be as straightforward as initially thought, was provided by Fredholm et al. (2016) who reported that " the deletion in NHEJ1 is not predictive for CH [choroidal hypoplasia] in the Danish Rough Collie population, whereas the clinical and genetic diagnosis is in accordance with each other in the Shetland Sheepdog population. Based on these results, it can be concluded that the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations but linked to both the wild-type and CH-causing locus in most dogs in the Danish Rough Collie population." Further doubt on the causality of the deletion was raised by the results of Brown et al. (2018) in Nova Scotia Duck Tolling Retrievers. Grosås et al. (2018) reported "A good compliance between the clinical diagnosis and the genetic test results was found" in 103 puppies from a random sample of 16 unrelated Norwegian Border Collie litters. The authors reported that one puppy was clinically affected and one puppy was homozygous for the deletion variant, but intriguingly, readers were not told whether this was the same puppy. Also, even though the parents were genotyped, readers were not told whether the parents of the affected puppy were both heterozygotes.

Clinical features: CEA presents as varying levels of visual impairment, from no visual impairment to complete blindness. As summarised by Fredholm et al. (2016), "Collie eye anomaly (CEA) is a congenital, inherited ocular disorder which is widespread in herding breeds. Clinically, the two major lesions associated with CEA are choroidal hypoplasia (CH) and coloboma, and both lesions are diagnosed based on ophthalmological examination". Choroidal hypoplasia is noted as a defect in the ocular fundus temporal to the optic nerve, which can be detected during ophthalmoscopic exam. Some affected dogs have tortuous retinal vessels and multiple retinal folds. More severely affected dogs can develop retinal detachments leading to blindness. These dogs can also develop subretinal and preretinal neovascularization and intraocular hemorrhage (Lowe et al., 2003).

Pathology: The choroid is the vascular supply to the retina. The primary defect in this disorder is choroidal hypoplasia. Secondary lesions include colobomas around and in the optic nerve head or the adjacent fundus. Retinal detachment is also a secondary lesion.

Prevalence: Prevalence is estimated to be 70-97% in rough and smooth collies in the USA and Great Britain, and 68% in rough collies in Sweden. In Border collies, prevalence is estimated at 2-3% in the USA and Great Britain (Lowe et al., 2003). Mizukami et al. (2016) reported the frequency of the NHEJ1 deletion allele as 0.143 in 500 Border collies in Japan. Grosås et al. (2018) reported the frequency of the deletion variant as 6.3% in Norwegian Border Collies. In a sample of 465 Italian dogs from five breeds, Marelli et al. (2022) reported that the frequency of carriers (healthy heterozygotes) for the deletion variant (OMIA variant 632) was 50% in Shetland Sheepdog, 45% in Nova Scotia Duck Tolling Retriever, 30% in Border Collie, 17% in Australian Shepherd, and 13% in Rough Collies. Donner et al. (2018) reported that the variant (OMIA variant 632) was identified in additional breeds and reported carrier frequencies: Australian Kelpie: 7.5% (6/80), Chinook: 0.7% (1/151), Jack Russell Terrier: 3.8% (4/105), Parson Russell Terrier: 1.2% (3/243), Koolie: 41% (16/39), Lapponian Herder: 5% (1/20), Tamaskan Dog: 3.5% (3/86) Clark et al. (2023) "utilized a large set of genotypes from dogs tested for the progressive rod-cone degeneration–progressive retinal atrophy (prcd-PRA) G>A missense PRCD variant (n = 86,667) and the collie eye anomaly (CEA)-associated NHEJ1 deletion (n = 33,834) ... . ... the NHEJ1 deletion may actually be linked to the true causal mutation, as the deletion does not segregate with coloboma or CH in some cases ... . Regression modeling showed time progression to significantly affect the odds of a dog being homozygous or heterozygous for either [variant], as do variables including breed and breed popularity. This study shows that genetic testing informed breeding decisions to produce fewer affected dogs. However, the presence of dogs homozygous for the disease variant, especially for prcd-PRA, was still observed fourteen years after test availability, potentially due to crosses of unknown carriers."

Genetic testing: For limitations on the utility of testing for the published likely causal variant, see the results of Fredholm et al. (2016) and Brown et al. (2018).

Breeds: Alaskan Husky (Dog) (VBO_0200015), Australian Kelpie (Dog) (VBO_0200090), Australian Shepherd (Dog) (VBO_0200095), Border Collie (Dog) (VBO_0200193), Boykin Spaniel (Dog) (VBO_0200214), Chinook (Dog) (VBO_0200353), Collie Rough (Dog) (VBO_0200376), Collie Smooth (Dog) (VBO_0200377), Hokkaido (Dog) (VBO_0200671), Jack Russell Terrier (Dog) (VBO_0200724), Koolie (Dog) (VBO_0200782), Lancashire Heeler (Dog) (VBO_0200808), Lapponian Herder (Dog) (VBO_0200814), Long-Haired Whippet (Dog) (VBO_0200833), Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964), Old English Sheepdog (Dog) (VBO_0200969), Parson Russell Terrier (Dog) (VBO_0200987), Shetland Sheepdog (Dog) (VBO_0201217), Siberian Husky (Dog) (VBO_0201233), Silken Windhound (Dog) (VBO_0201235), Smithfield (Dog) (VBO_0201256), Tamaskan Dog (Dog) (VBO_0201334).
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: