Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs.

Letko, Anna; Leuthard, Fabienne; Jagannathan, Vidya; Corlazzoli, Daniele; Matiasek, Kaspar; Schweizer, Daniela; Hytönen, Marjo K; Lohi, Hannes; Leeb, Tosso; Drögemüller, Cord (2020). Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs. Genes, 11(2) MDPI, Molecular Diversity Preservation International 10.3390/genes11020163

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Clinical Radiology
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Letko, Anna; Leuthard, Fabienne Nadja; Jagannathan, Vidya; Schweizer, Daniela Esther; Leeb, Tosso and Drögemüller, Cord

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
600 Technology > 610 Medicine & health

ISSN:

2073-4425

Publisher:

MDPI, Molecular Diversity Preservation International

Language:

English

Submitter:

Cord Drögemüller

Date Deposited:

14 Feb 2020 09:18

Last Modified:

14 Feb 2020 09:18

Publisher DOI:

10.3390/genes11020163

PubMed ID:

32033218

Uncontrolled Keywords:

COL1A1 Caffey disease SLC35D1 SLC37A2 calvarial hyperostotic syndrome craniomandibular osteopathy infantile cortical hyperostosis rare disease whole-genome sequencing

BORIS DOI:

10.7892/boris.140069

URI:

https://boris.unibe.ch/id/eprint/140069

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