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Open AccessArticle

Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs

1
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
2
Clinica Veterinaria Roma Sud, 00173 Roma, Italy
3
Section of Clinical & Comparative Neuropathology, Centre for Clinical Veterinary Medicine, Ludwig Maximilians Universität Munich, 80539 Munich, Germany
4
Division of Clinical Radiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
5
Department of Medical and Clinical Genetics, and Department of Veterinary Biosciences, University of Helsinki, 00014 Helsinki, Finland
6
Folkhälsan Research Center, 00290 Helsinki, Finland
*
Author to whom correspondence should be addressed.
Genes 2020, 11(2), 163; https://doi.org/10.3390/genes11020163
Received: 15 November 2019 / Revised: 14 January 2020 / Accepted: 31 January 2020 / Published: 4 February 2020
(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)
Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.
Keywords: whole-genome sequencing; craniomandibular osteopathy; calvarial hyperostotic syndrome; Caffey disease; infantile cortical hyperostosis; rare disease; SLC37A2; COL1A1; SLC35D1 whole-genome sequencing; craniomandibular osteopathy; calvarial hyperostotic syndrome; Caffey disease; infantile cortical hyperostosis; rare disease; SLC37A2; COL1A1; SLC35D1
MDPI and ACS Style

Letko, A.; Leuthard, F.; Jagannathan, V.; Corlazzoli, D.; Matiasek , K.; Schweizer, D.; Hytönen, M.K.; Lohi, H.; Leeb , T.; Drögemüller , C. Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs. Genes 2020, 11, 163.

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