A naturally-occurring canine model of congenital microphthalmia with multisystemic features

Abstract

Purpose : Ocular maldevelopment is responsible for 30% of global vision impairment and blindness. Still, due to the wide phenotypic spectrum, including multisystemic features, along with unknown or complex etiology and unclear pathogenesis, these congenital disorders pose a major diagnostic challenge, with treatment options limited to symptomatic or supportive care. Congenital microphthalmos occurs in 1/10,000 individuals, with extra-ocular involvement reported in ~80% of cases. Here, we describe a naturally-occurring canine model of hereditary complex ocular-multisystem disorder, canine Congenital Microphthalmos with Hematopoietic Defect (cCMHD), and characterize the clinical and molecular basis of this newly-recognized syndrome in Portuguese water dogs.

Methods : A total of 68 privately owned dogs (42 affected and 26 non-affected relatives; age range: 0.5-75 months) were enrolled in the study. A physical examination and ophthalmologic assessments were performed; blood samples were collected for CBC and serum biochemistry screens and/or processed for molecular studies.

Results : Bilateral microphthalmia associated with anterior segment dysgenesis (cataract, corneal dystrophy, and persistent pupillary membrane) were present in all dogs along with retinal detachment in some. Hematologic abnormalities such as thrombocytopenia with normocytic normochromic anemia were present in the affected dogs. To a lesser extent, the oculo-hematologic phenotype was accompanied by enamel hypoplasia and delayed tooth eruption, growth retardation, and infertility. Pedigree analysis indicated an autosomal recessive pattern of inheritance. A genome-wide association study and homozygosity mapping led to the identification of a 5-Mb candidate region on CFA4. Fine-mapping and screening of functional candidate genes are ongoing.

Conclusions : We describe a newly recognized, autosomal recessive disorder cCMHD, characterized by complex eye malformations in association with hematologic and non-hematologic abnormalities. This spontaneous canine model constitutes a valuable research platform toward mechanistic studies of the developmental abnormalities, and the potential development of specific therapies for this group of human multisystemic conditions.

This is a 2020 ARVO Annual Meeting abstract.