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Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs

BACKGROUND: Globoid cell leukodystrophy (GCL) is a fatal autosomal recessive disease caused by variants in the galactosylceramidase (GALC) gene. Two dog breed‐specific variants are reported. OBJECTIVES: Characterize the putatively causative GALC variant for GCL in a family of dogs and determine popu...

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Autores principales: Hammack, Samantha, Hague, Devon Wallis, Vieson, Miranda D., Esdaile, Elizabeth, Hughes, Shayne S., Bellone, Rebecca R., McCoy, Annette M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473001/
https://www.ncbi.nlm.nih.gov/pubmed/37593836
http://dx.doi.org/10.1111/jvim.16822
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author Hammack, Samantha
Hague, Devon Wallis
Vieson, Miranda D.
Esdaile, Elizabeth
Hughes, Shayne S.
Bellone, Rebecca R.
McCoy, Annette M.
author_facet Hammack, Samantha
Hague, Devon Wallis
Vieson, Miranda D.
Esdaile, Elizabeth
Hughes, Shayne S.
Bellone, Rebecca R.
McCoy, Annette M.
author_sort Hammack, Samantha
collection PubMed
description BACKGROUND: Globoid cell leukodystrophy (GCL) is a fatal autosomal recessive disease caused by variants in the galactosylceramidase (GALC) gene. Two dog breed‐specific variants are reported. OBJECTIVES: Characterize the putatively causative GALC variant for GCL in a family of dogs and determine population allele frequency. ANIMALS: Four related mixed‐breed puppies with signs of neurologic disease were evaluated. Subsequently, 33 related dogs were tested for genetic markers for parentage and the identified GALC variant. Additional GALC genotyping was performed on 278 banked samples from various breeds. METHODS: The 4 affected puppies had neurological exams and necropsies. DNA was isolated from blood samples. Variants in GALC were identified via Sanger sequencing. Parentage testing was performed using short tandem repeat markers. Prevalence of the GALC variant of interest was investigated in other breeds. RESULTS: GCL was confirmed histopathologically. A novel missense variant in GALC (NC_006590.4:g.58893972G>A) was homozygous in all affected animals (n = 4). A recessive mode of inheritance was confirmed by parentage testing as was variant linkage with the phenotype (LOD = 3.36). Among the related dogs (n = 33), 3 dogs were homozygous and 7 heterozygous. The variant allele was not detected in screening 278 dogs from 5 breeds. The novel variant is either unique to this family or has an extremely low allele frequency in the general population. CONCLUSIONS AND CLINICAL IMPORTANCE: A novel GALC variant was identified that likely explains GCL in this cohort. The identification of multiple causal variants for GCL in dogs is consistent with findings in humans.
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spelling pubmed-104730012023-09-02 Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs Hammack, Samantha Hague, Devon Wallis Vieson, Miranda D. Esdaile, Elizabeth Hughes, Shayne S. Bellone, Rebecca R. McCoy, Annette M. J Vet Intern Med SMALL ANIMAL BACKGROUND: Globoid cell leukodystrophy (GCL) is a fatal autosomal recessive disease caused by variants in the galactosylceramidase (GALC) gene. Two dog breed‐specific variants are reported. OBJECTIVES: Characterize the putatively causative GALC variant for GCL in a family of dogs and determine population allele frequency. ANIMALS: Four related mixed‐breed puppies with signs of neurologic disease were evaluated. Subsequently, 33 related dogs were tested for genetic markers for parentage and the identified GALC variant. Additional GALC genotyping was performed on 278 banked samples from various breeds. METHODS: The 4 affected puppies had neurological exams and necropsies. DNA was isolated from blood samples. Variants in GALC were identified via Sanger sequencing. Parentage testing was performed using short tandem repeat markers. Prevalence of the GALC variant of interest was investigated in other breeds. RESULTS: GCL was confirmed histopathologically. A novel missense variant in GALC (NC_006590.4:g.58893972G>A) was homozygous in all affected animals (n = 4). A recessive mode of inheritance was confirmed by parentage testing as was variant linkage with the phenotype (LOD = 3.36). Among the related dogs (n = 33), 3 dogs were homozygous and 7 heterozygous. The variant allele was not detected in screening 278 dogs from 5 breeds. The novel variant is either unique to this family or has an extremely low allele frequency in the general population. CONCLUSIONS AND CLINICAL IMPORTANCE: A novel GALC variant was identified that likely explains GCL in this cohort. The identification of multiple causal variants for GCL in dogs is consistent with findings in humans. John Wiley & Sons, Inc. 2023-08-18 /pmc/articles/PMC10473001/ /pubmed/37593836 http://dx.doi.org/10.1111/jvim.16822 Text en © 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle SMALL ANIMAL
Hammack, Samantha
Hague, Devon Wallis
Vieson, Miranda D.
Esdaile, Elizabeth
Hughes, Shayne S.
Bellone, Rebecca R.
McCoy, Annette M.
Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
title Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
title_full Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
title_fullStr Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
title_full_unstemmed Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
title_short Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
title_sort novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs
topic SMALL ANIMAL
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473001/
https://www.ncbi.nlm.nih.gov/pubmed/37593836
http://dx.doi.org/10.1111/jvim.16822
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