PT  - JOURNAL ARTICLE
AU  - Carys A Pugh
AU  - Lindsay L Farrell
AU  - Ailsa J Carlisle
AU  - Stephen J Bush
AU  - Violeta Trejo-Reveles
AU  - Oswald Matika
AU  - Arne de Kloet
AU  - Caitlin Walsh
AU  - Stephen C Bishop
AU  - James GD Prendergast
AU  - Jeffrey J Schoenebeck
AU  - Joe Rainger
AU  - Kim M Summers
TI  - Arginine to glutamine mutation in olfactomedin-like 3 (<em>OLFML3</em>) is a candidate for severe goniodysgenesis and glaucoma in the Border Collie dog breed
AID  - 10.1101/321406
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 321406
4099  - http://biorxiv.org/content/early/2018/05/14/321406.short
4100  - http://biorxiv.org/content/early/2018/05/14/321406.full
AB  - Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (Canis lupus familiaris), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and has subsequently been found in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine SNP chip and whole genome sequencing was used to identify candidate genetic regions. Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. There was a highly significant peak of association over chromosome 17, with a p -value of 2 × 10-13. Whole genome sequences of three dogs with glaucoma, three with severe goniodysgenesis and three unaffected dogs identified a missense variant in the olfactomedin-like 3 (OLFML3) gene in all six affected animals. This was homozygous in all nine cases with glaucoma and nine of 11 other severely affected animals. None of 56 unaffected animals was homozygous for this variant. The identification of a candidate genetic region and putative causative mutation will inform breeding programs to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population.