@article{olby_friedenberg_meurs_deprospero_guevar_lau_yost_guo_shelton_2020, title={A mutation in MTM1 causes X-Linked myotubular myopathy in Boykin spaniels}, volume={30}, ISSN={0960-8966}, url={http://dx.doi.org/10.1016/j.nmd.2020.02.021}, DOI={10.1016/j.nmd.2020.02.021}, abstractNote={The purpose of this study was to report the findings of clinical and genetic evaluation of a 3-month old male Boykin spaniel (the proband) that presented with progressive weakness. The puppy underwent a physical and neurological examination, serum biochemistry and complete blood cell count, electrophysiological testing, muscle biopsy and whole genome sequencing. Clinical evaluation revealed generalized neuromuscular weakness with tetraparesis and difficulty holding the head up and a dropped jaw. There was diffuse spontaneous activity on electromyography, most severe in the cervical musculature. Nerve conduction studies were normal, the findings were interpreted as consistent with a myopathy. Skeletal muscle was grossly abnormal on biopsy and there were necklace fibers and abnormal triad structure localization on histopathology, consistent with myotubular myopathy. Whole genome sequencing revealed a premature stop codon in exon 13 of MTM1 (ChrX: 118,903,496 C > T, c.1467C>T, p.Arg512X). The puppy was humanely euthanized at 5 months of age. The puppy's dam was heterozygous for the variant, and 3 male puppies from a subsequent litter all of which died by 2 weeks of age were hemizygous for the variant. This naturally occurring mutation in Boykin spaniels causes a severe form of X-linked myotubular myopathy, comparable to the human counterpart.}, number={5}, journal={Neuromuscular Disorders}, publisher={Elsevier BV}, author={Olby, Natasha J. and Friedenberg, Steven and Meurs, Kathryn and DeProspero, Dylan and Guevar, Julien and Lau, Jeanie and Yost, Oriana and Guo, Ling T. and Shelton, G. Diane}, year={2020}, month={Mar}, pages={353–359} }
 @article{meurs_friedenberg_kolb_saripalli_tonino_woodruff_olby_keene_adin_yost_et al._2019, title={A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death}, volume={138}, ISSN={0340-6717 1432-1203}, url={http://dx.doi.org/10.1007/s00439-019-01973-2}, DOI={10.1007/s00439-019-01973-2}, abstractNote={The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.}, number={5}, journal={Human Genetics}, publisher={Springer Science and Business Media LLC}, author={Meurs, Kathryn M. and Friedenberg, Steven G. and Kolb, Justin and Saripalli, Chandra and Tonino, Paola and Woodruff, Kathleen and Olby, Natasha J. and Keene, Bruce W. and Adin, Darcy B. and Yost, Oriana L. and et al.}, year={2019}, month={Feb}, pages={515–524} }
 @article{friedenberg_vansteenkiste_yost_treeful_meurs_tokarz_olby_2018, title={A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers}, volume={32}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/jvim.15073}, DOI={10.1111/jvim.15073}, abstractNote={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.}, number={3}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Friedenberg, Steven G. and Vansteenkiste, Daniella and Yost, Oriana and Treeful, Amy E. and Meurs, Kathryn M. and Tokarz, Debra A. and Olby, Natasha J.}, year={2018}, month={Feb}, pages={986–992} }
 @article{guevar_olby_meurs_yost_friedenberg_2018, title={Deafness and vestibular dysfunction in a Doberman Pinscher puppy associated with a mutation in the PTPRQ
 gene}, volume={32}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/jvim.15060}, DOI={10.1111/jvim.15060}, abstractNote={BackgroundA congenital syndrome of hearing loss and vestibular dysfunction affects Doberman Pinschers. Its inheritance pattern is suspected to be autosomal recessive and it potentially represents a spontaneous animal model of an autosomal recessive syndromic hearing loss.Hypothesis/ObjectivesThe objectives of this study were to use whole genome sequencing (WGS) to identify deleterious genetic variants in candidate genes associated with the syndrome and to study the prevalence of candidate variants among a population of unaffected Doberman Pinschers.AnimalsOne affected Doberman Pinscher and 202 unaffected Doberman Pinschers.MethodsWGS of the affected dog with filtering of variants against a database of 154 unaffected dogs of diverse breeds was performed. Confirmation of candidate variants was achieved by Sanger sequencing followed by genotyping of the control population of unaffected Doberman Pinschers.ResultsWGS and variant filtering identified an alteration in a gene associated with both deafness and vestibular disease in humans: protein tyrosine phosphatase, receptor type Q (PTPRQ). There was a homozygous A insertion at CFA15: 22 989 894, causing a frameshift mutation in exon 39 of the gene. This insertion is predicted to cause a protein truncation with a premature stop codon occurring after position 2054 of the protein sequence that causes 279 C‐terminal amino acids to be eliminated. Prevalence of the variant was 1.5% in a cohort of 202 unaffected Doberman Pinschers; all unaffected Doberman Pinschers were heterozygous or heterozygous for the reference allele.Conclusion and Clinical ImportanceWe report the identification of a genetic alteration on the PTPRQ gene that is associated with congenital hearing and vestibular disorder in a young Doberman Pinscher dog.}, number={2}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Guevar, Julien and Olby, Natasha J. and Meurs, Kathryn M. and Yost, Oriana and Friedenberg, Steven G.}, year={2018}, month={Feb}, pages={665–669} }