Frameshift variant in AMPD2 in Cirneco dell’ Etna with retinopathy and tremors

Many retinal conditions have non-syndromic manifestations, but many can be part of a syndrome.  The majority of these syndromic retinal disorders are thought to be recessively inherited. Several tissues are affected other than the retina, including the nervous system. A litter of four Cirneco dogs, all males, show signs of retinal degeneration, along with tremors and signs that could be described preliminarily as atypical seizures or paroxysmal dyskinesias. The other two littermates were normal. A genetic etiology for this oculo-neurological syndrome was suspected, which we named CONS (Cirneco Oculo-neurological syndrome). Homozygosity mapping and whole-genome sequencing detected in CFA6 a 1-bp deletion in the canine AMPD2, an adenosine monophosphate deaminase converting adenosine 5'-monophosphate (AMP) and to inosine 5'-monophosphate (IMP), causing a frameshift and premature stop codon. Genotyping of the available Cirneco population suggests perfect segregation between cases and controls for the variant, which is also absent in thousands of unaffected dogs in canine genomic databases. AMPD2 mutation we propose adds to the spectrum of neurological manifestations associated with AMPD2, in a canine model which also presents retinal manifestations, therefore expanding the phenotype spectrum.

Methods
SNPdata: genotype data Type from 220k CanineHD array (Illumina). DNA was extracted from blood and processed by Neogen.

NovaSeq6000 paired-end reads (2x100 bp)  whole genome sequencing (as for company instructions). The PCR-free library was prepared as follows. Libraries of 300 bp insert size were prepared and Illumina NovaSeq6000 paired-end reads (2 × 100 bp) were collected. Fastq files were generated using Casava 1.8. A total of 1,521,125,559 reads (100 bp paired-end reads) were collected in total for the sequenced dogs (corresponding to an approximate average coverage of the genome of 32× for VB260 and 45× for V259.