A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers

Abstract

BackgroundWe aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies.HypothesisWe hypothesized that the associated mutation would be located in a gene that causes osteochondromatosis in humans.AnimalsA litter of 9 American Staffordshire puppies, their sire and dam, 3 of 4 grandparents, 26 healthy unrelated American Staffordshire Terriers, and 154 dogs of 27 different breeds.MethodsWhole genome sequencing was performed on the proband, and variants were compared against polymorphisms derived from 154 additional dogs across 27 breeds, as well as single nucleotide polymorphism database 146. One variant was selected for follow‐up sequencing. Parentage and genetic mosaicism were evaluated across the litter.ResultsWe found 56,301 genetic variants unique to the proband. Eleven variants were located in or near the gene exostosin 2 (EXT2), which is strongly associated with osteochondromatosis in humans. One heterozygous variant (c.969C > A) is predicted to result in a stop codon in exon 5 of the gene. Sanger sequencing identified the identical mutation in all affected offspring. The mutation was absent in the unaffected offspring, both parents, all available grandparents, and 26 healthy unrelated American Staffordshire Terriers.Conclusions and Clinical ImportanceThese findings represent the first reported mutation associated with osteochondromatosis in dogs. Because this mutation arose de novo, the identical mutation is unlikely to be the cause of osteochondromatosis in other dogs. However, de novo mutations in EXT2 are common in humans with osteochondromatosis, and by extension, it is possible that dogs with osteochondromatosis could be identified by sequencing the entire EXT2 gene.

Multiple cartilaginous exostoses in a Swiss Mountain dog causing thoracolumbar compressive myelopathy

“…MCE usually expands in the thoracolumbar vertebral column. The appearance and severity of the clinical signs depends on the localization of exostoses and their size [8]. Few reports of MCE with secondary myelopathy have been published in veterinary medicine, and its etiology has not been fully clarified.…”

“…This procedure prevented sudden decompensation and deterioration of the neurological status of the dog. Early surgical intervention may eliminate the evolution of clinical complications and eradicate a latent threat of malignancy in older dogs [8]. The nervous tissue is resistant to damaging effects of gradual compression, and severe compression is tolerated until sudden decompensation [13].…”

“…It has been suggested [19, 24] that surgical removal may be less challenging when the MCE are less developed, softer and with less vascularization. The lesions stop expanding as the animal matures, whereby the cancellous bone becomes harder and more vascular [8, 19, 24]. Prognosis is guarded, especially in young dogs with multiple vertebral involvement, where subclinical lesions may grow until the skeleton matures.…”

“…Recently, a de novo mutation in the EXT2 gene was reported in a litter of American Staffordshire Terrier dogs with MCE. This gene is strongly associated with MCE in humans [8]. While the growth of most exostoses discontinues as the animal matures, some lesions may undergo neoplastic transformation as was observed in a group of adult dogs over 7 years old [7].…”

Multiple Cartilaginous Exostoses Causing Severe Cervical Myelopathy in a Puppy Dog

“…Multiple cartilaginous exostoses (MCE), also known as osteochondromatosis, is a rare hereditary disorder of skeletal development associated with mutation of the genes exostosin 1 or 2, described in humans, horses, dogs and cats. [1][2][3][4][5] The excessive cartilaginous proliferation can occur in the metaphysis of long bones causing irregular bone formation on bone surfaces. 3,4 When MCE masses affect the vertebrae, spinal cord compression and gait disorders may occur.…”