Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 310600 (trait) , 300658 (gene) , 305390 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Inheritance: Pedigree analysis in a small family was consistent with an X-linked recessive mode of inheritance (Joyce et al., 2021).

Molecular basis: One affected dog was whole genome sequenced, followed by analysis using a candidate gene approach (COL9A2, COL9A3, NHEJ1, RS1 and NDP genes) and a whole genome approach (WGS was compared with 814 unaffected canids to identify candidate variants). "Candidate variants were tested for appropriate segregation in the ECS family and association with disease was assessed using samples from a total of 180 ECS. ... The same variant in NDP (c.653_654insC, p.Met114Hisfs*16) that was predicted to result in 15 aberrant amino acids before a premature stop in norrin protein, was identified independently by both approaches and was shown to segregate appropriately within the ECS family." (Joyce et al., 2021)

Clinical features: Joyce et al. (2021): "In the original litter examined (seven puppies), two males were found to have behavioural signs suggestive of severe visual deficits (determined by observing their movements in unfamiliar surroundings), absent pupillary light reflexes, wandering nystagmus, darkened irises, and extensive posterior segment haemorrhage. Ocular ultrasonography revealed total retinal detachment and increased echogenicity within posterior segment in all eyes. The globe diameters (anterior to posterior) were comparable with their normal litter mates at 16mm in all dogs except one affected dog, whose globes were 15mm OU. ... One male was found to be bilaterally cryptorchid on clinical examination. ... In the second litter examined (four puppies), one male displayed behavioural signs suggestive of severe visual deficits (determined by observing his movements in unfamiliar surroundings), and was found to have absent dazzle and pupillary light reflexes, a wandering nystagmus, corneal endothelial opacities ventrally in the right eye, darkened irises, hyphema of the right eye and extensive posterior segment haemorrhage in both eyes, with the retina in the left eye appearing detached and as a fibrovascular retrolental mass ..... Ocular ultrasonography revealed total retinal detachment and increased echogenicity within the posterior segment in both eyes. The left globe appeared microphthalmic with an anterior-posterior diameter of 16.42mm versus 21.88mm in the right eye. The affected male was subsequently re-examined, the left eye appeared relatively unchanged whereas the corneal pathology had advanced to diffuse corneal degeneration with neovascularisation and dense crystalline stromal deposits in the right eye .... Microphakia was evident along with incipient nuclear cataract being present ... . On clinical examination the dog was found to be cryptorchid at 10 months old."

Breed: English Cocker Spaniel (Dog) (VBO_0200486).
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: