Frameshift variant in the Cirneco dell’Etna dog with syndromic retinopathy and tremors

Abstract

Purpose : While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, often the nervous system. Most syndromic retinal disorders are thought to be recessively inherited. Two male dogs from a litter of Cirneco dell’ Etna, a rare breed of Italian Pharaoh-hound type dogs, showed tremors and signs described as either atypical seizures or paroxysmal dyskinesias. The other two male littermates were clinically normal, and so were the parents. A genetic etiology was suspected for this oculo-neurological syndrome, which we have named CONS (Cirneco Oculo-Neurological Syndrome). The aim of this study was to further characterize the phenotype and identify the putative genetic basis of this syndrome.

Methods : MRI of the brain and cervical spinal cord, followed by cerebrospinal fluid analysis was performed alongside clinical examinations. Homozygosity mapping was carried out using Illumina 220k SNP-chip of the two cases and thirty-five related and unrelated controls, highlighting seven candidate regions. Whole genome sequencing was performed for the two cases, searching into the candidate regions. The Dog10k canine variants database was used to filter out non-exclusive genetic variants.

Results : MRI showed reduced cerebral white matter volume and in one case a T2 hyperintensity. CSF taps were unremarkable. We detected a 1-bp deletion in CFA6 predicted to cause a frameshift and premature stop codon within the canine AMPD2 gene, which encodes adenosine monophosphate deaminase, an enzyme that converts adenosine 5'-monophosphate (AMP) to inosine 5'-monophosphate (IMP) and is known to cause. Genotyping of the available Cirneco population suggests perfect segregation between cases and controls for the variant. Population studies suggests the variant is limited to the breed.

Conclusions : The AMPD2 genetic variant we identified in canines presents with novel retinal manifestations, adding to the spectrum of neurological manifestations associated with AMPD2 variants in humans, which are primarily pontocerebellar hypoplasia (PCH) and spastic paraplegia.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.