Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs - PubMed (original) (raw)

. 2023 Sep-Oct;37(5):1710-1715.

doi: 10.1111/jvim.16822. Epub 2023 Aug 18.

Affiliations

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

Samantha Hammack et al. J Vet Intern Med. 2023 Sep-Oct.

Abstract

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.

Keywords: GALC; Krabbe disease; canine; congenital disease; neurologic disease.

© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.

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Conflict of interest statement

Authors declare no conflict of interest.

Figures

FIGURE 1

FIGURE 1

Gross appearance of brains from the 3 affected dogs examined at the same time. The middle brain was from the most severely clinically affected dog. It is grossly smaller than the other 2 and has flattened cerebral gyri and a thinner brainstem.

FIGURE 2

FIGURE 2

Photomicrograph of cerebral cortical white matter with plump globoid macrophages (arrowheads) filled by Periodic acid‐Schiff‐positive material (inset) infiltrating perivascular spaces and scattered in the neuropil of 1 of the affected dogs. H&E stain.

FIGURE 3

FIGURE 3

Proposed relationships between dogs included in the study cohort based on parentage analysis. Two unaffected individuals could not be placed within this family organization. Dogs #21‐23 were from litters born in late 2017; the remainder of the offspring from these same matings were born in early 2019. Solid fill = homozygous for novel variant and showing clinical signs of disease; dogs labeled with an X are those confirmed affected with globoid cell leukodystrophy based on histopathology. Partially filled = heterozygous for novel variant (carriers). Open = homozygous for reference allele. Dogs labeled with a question mark (?) have proposed genotypes based on mode of inheritance but their identity is unknown. * Two dams qualify with 0/48 exclusions for the trio (#30 and #29). The sample was placed on this pedigree as offspring of #30 because potential littermates are the same age.

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