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Understanding phenotype–genotype correlations in retinal degeneration is a major challenge. Mutations in  CRB1  lead to a spectrum of autosomal recessive retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the  Crb1 rd8/rd8   mutation, we compared the retinal pathology of  Crb1 rd8/rd8 /J  inbred mice with that of two  Crb1 rd8/rd8   lines backcrossed with  C57BL/6JOlaHsd  mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three  Crb1 rd8/rd8   lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Müller and microglia activation and telangiectasia-like vascular remodelling—features that were stable in the inbred, variable in the second, but virtually absent in the third  Crb1 rd8/rd8   line, even at 12 months of age. This suggests that the  Crb1 rd8/rd8   mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype–phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the retinal pathology associated with mutations in  Crb1.  This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with  CRB1  mutations that are thought to depend on such genetic modifiers.

The severity of retinal pathology in homozygous Crb1 rd8/rd8 mice is dependent on additional genetic factors