Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs

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Letko , A , Leuthard , F , Jagannathan , V , Corlazzoli , D , Matiasek , K , Schweizer , D , Hytönen , M K , Lohi , H , Leeb , T & Droegemueller , C 2020 , ' Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs ' , Genes , vol. 11 , no. 2 , 163 . https://doi.org/10.3390/genes11020163

Title: Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs
Author: Letko, Anna; Leuthard, Fabienne; Jagannathan, Vidhya; Corlazzoli, Daniele; Matiasek, Kaspar; Schweizer, Daniela; Hytönen, Marjo K.; Lohi, Hannes; Leeb, Tosso; Droegemueller, Cord
Contributor: University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Biosciences
Date: 2020-02
Language: eng
Number of pages: 12
Belongs to series: Genes
ISSN: 2073-4425
URI: http://hdl.handle.net/10138/313950
Abstract: 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.
Subject: whole-genome sequencing
craniomandibular osteopathy
calvarial hyperostotic syndrome
Caffey disease
infantile cortical hyperostosis
rare disease
CAFFEY-DISEASE
CRANIOMANDIBULAR OSTEOPATHY
CORTICAL HYPEROSTOSIS
COL1A1 MUTATION
ANIMAL-MODEL
IDENTIFICATION
GENE
413 Veterinary science
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