Identification of a variant in NDP associated with X-linked retinal dysplasia in the English cocker spaniel dog

PLoS One. 2021 May 4;16(5):e0251071. doi: 10.1371/journal.pone.0251071. eCollection 2021.

Abstract

Purpose: Three related male English Cocker Spaniels (ECS) were reported to be congenitally blind. Examination of one of these revealed complete retinal detachment. A presumptive diagnosis of retinal dysplasia (RD) was provided and pedigree analysis was suggestive of an X-linked mode of inheritance. We sought to investigate the genetic basis of RD in this family of ECS.

Methods: Following whole genome sequencing (WGS) of the one remaining male RD-affected ECS, two distinct investigative approaches were employed: a candidate gene approach and a whole genome approach. In the candidate gene approach, COL9A2, COL9A3, NHEJ1, RS1 and NDP genes were investigated based on their known associations with RD and retinal detachment in dogs and humans. In the whole genome approach, affected WGS was compared with 814 unaffected canids to identify candidate variants, which were filtered based on appropriate segregation and predicted pathogenic effects followed by subsequent investigation of gene function. 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.

Results: 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. Association of this variant with X-linked RD was significant (P = 0.0056).

Conclusions: For the first time, we report a variant associated with canine X-linked RD. NDP variants are already known to cause X-linked RD, along with other abnormalities, in human Norrie disease. Thus, the dog may serve as a useful large animal model for research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blindness / congenital
  • Blindness / genetics
  • Dog Diseases / genetics*
  • Dogs
  • Eye Proteins / genetics*
  • Genes, X-Linked / genetics*
  • Genetic Diseases, X-Linked / genetics
  • Male
  • Nerve Tissue Proteins / genetics*
  • Nervous System Diseases / genetics
  • Pedigree
  • Phenotype
  • Retinal Degeneration / genetics
  • Retinal Detachment / genetics
  • Retinal Dysplasia / genetics*

Substances

  • Eye Proteins
  • Nerve Tissue Proteins

Supplementary concepts

  • Norrie disease

Grant support

The work was supported by the Animal Health Trust, the Kennel Club Charitable Trust and the British Association of Veterinary Ophthalmologists (BrAVO). Two of the funders provided support in the form of salaries for authors HJ and LF (Animal Health Trust) and LMB, HW, and CM (Kennel Club Charitable Trust), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Three of the authors (HJ, LF and JO) are currently employed by a commercial company, Dick White Referrals, but this affiliation did not play a role in the study as the authors were based at the Animal Health Trust at the time of their contribution to this study. Dick White Referrals are not a funder of this study and had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The BrAVO Research grant awarded to the main author, HJ, for the whole genome analysis of the affected case was for solely this and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. https://www.bravo.org.uk