TY - JOUR
T1 - A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers
AU - Friedenberg, Steven G.
AU - Vansteenkiste, Daniella
AU - Yost, Oriana
AU - Treeful, Amy E.
AU - Meurs, Kathryn M.
AU - Tokarz, Debra A.
AU - Olby, Natasha J.
N1 - Publisher Copyright:
Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Background: We aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies. Hypothesis: We hypothesized that the associated mutation would be located in a gene that causes osteochondromatosis in humans. Animals: A 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. Methods: Whole 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. Results: We 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 Importance: These 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.
AB - Background: We aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies. Hypothesis: We hypothesized that the associated mutation would be located in a gene that causes osteochondromatosis in humans. Animals: A 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. Methods: Whole 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. Results: We 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 Importance: These 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.
KW - bone
KW - cartilage
KW - genetics
KW - multiple cartilaginous exostoses
KW - mutation
KW - osteochondroma
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U2 - 10.1111/jvim.15073
DO - 10.1111/jvim.15073
M3 - Article
C2 - 29485212
AN - SCOPUS:85047868036
SN - 0891-6640
VL - 32
SP - 986
EP - 992
JO - Journal of veterinary internal medicine
JF - Journal of veterinary internal medicine
IS - 3
ER -