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

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.

Identification of Selection Signals on the X-Chromosome in East Adriatic Sheep: A New Complementary Approach

“…The NDP and EFHC2 genes were found to range from 41.00 to 41.50 Mb. NDP (Norrin Cystine Knot Growth Factor NDP) encodes a secreted protein with a cysteine knot motif that activates the Wnt/beta-catenin signalling pathway and has been associated with dysplasia in dogs ( Joyce et al, 2021 ), whereas EFHC2 (EF-Hand Domain Containing 2) is associated with fear recognition and harm avoidance in humans ( Blaya et al, 2009 ). The iHS signal mapped from 42.50 to 43.00 Mb contains only the gene MIR221 (MicroRNA 221), which has been associated with the regulation of milk fat, protein synthesis, and mammary gland development in sheep ( Duman et al, 2021 ).…”