Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog.

Mucopolysaccharidosis (MPS) is a metabolic storage disorder caused by the deficiency of any lysosomal enzyme required for the breakdown of glycosaminoglycans. A 15-month-old Boston Terrier presented with clinical signs consistent with lysosomal storage disease including corneal opacities, multifocal central nervous system disease and progressively worsening clinical course. Diagnosis was confirmed at necropsy based on histopathologic evaluation of multiple organs demonstrating accumulation of mucopolysaccharides. Whole genome sequencing was used to uncover a frame-shift insertion affecting the alpha-L-iduronidase (IDUA) gene (c.19_20insCGGCCCCC), a mutation confirmed in another Boston Terrier presented 2 years later with a similar clinical picture. Both dogs were homozygous for the IDUA mutation and shared coat colors not recognized as normal for the breed by the American Kennel Club. In contrast, the mutation was not detected in 120 unrelated Boston Terriers as well as 202 dogs from other breeds. Recent inbreeding to select for recessive and unusual coat colors may have concentrated this relatively rare allele in the breed. The identification of the variant enables ante-mortem diagnosis of similar cases and selective breeding to avoid the spread of this disease in the breed. Boston Terriers carrying this variant represent a promising model for MPS I with neurological abnormalities in humans.

Comparative Cytogenetic Analysis of Dog and Human Choroid Plexus Tumors Defines Syntenic Regions of Genomic Loss.

Choroid plexus tumors (CPTs) occur spontaneously in humans and dogs providing an opportunity for comparative cross species analysis of common tumor mechanisms. Large scale chromosomal copy number alterations are the hallmark of human CPTs and identification of driver genes within these regions is problematic. Copy number alterations in 12 spontaneous dog CPTs were defined using an Illumina 170 K single nucleotide polymorphism array and were characterized by highly recurrent whole chromosomal losses in up to 100% of cases with few chromosome wide gains. Loss of canine chromosomes 2, 5, 8, and 20 were seen in 90%-100% of cases and included regions syntenic to loci within commonly reported whole chromosome losses in human choroid plexus tumors. These regions included previously defined tumor suppressor clusters on chromosome 3p and 17p as well as genes associated with chromosomal instability such as TP53 and VHL. This karyotypic signature is similar to a previously defined hypodiploid subgroup of human choroid plexus carcinomas. The nonrandom, highly recurrent alterations in dog CPTs suggest specific selection pressures and oncogenic mechanisms are present. More extensive analysis of this spontaneous tumor model is warranted and may provide key insights into driver mechanisms common to both species.