Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 610204 (trait) , 277470 (trait) , 225753 (trait) , 608755 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Inheritance: Störk et al. (2019): "The occurrence of leukodystrophy in multiple consecutive litters from related parents suggested an inherited disease. Pedigree analysis of the four affected puppies no. 1–4 revealed several inbreeding loops and was suggestive for a monogenic autosomal recessive inheritance".

Mapping: Linkage and homozygosity mapping of four affecteds, five normal littermates, and four parents of affecteds, each genotyped with an llumina CanineHD BeadChip, yielding 88,546 informative markers, enabled Störk et al. (2019) to identify "Eight [candidate] genomic segments on six different chromosomes with a total of 29,237,328 bp or roughly 1.2% of the 2.4 Gb dog genome".

Markers: Störk et al. (2019): "The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds."

Molecular basis: Comparison of private homozygous protein-changing variants in whole-genome sequence data from one affected dog with "control genome sequences from 8 wolves and 213 dogs" enabled Störk et al. (2019) to identify the likely causal variant as "a missense variant affecting exon 5 of the TSEN54 gene", namely "Chr9:5,015,506C>T (CanFam 3.1 assembly) . . . XM_540434.6:c.371G>A . . . XP_540434.3:p.(Gly124Asp)".

Clinical features: Störk et al. (2019): "Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect."

Pathology: Störk et al. (2019): "Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy." In humans, TSEN54 variants cause a phenotype termed pontocerebellar hypoplasia, which is quite distinct from the phenotype seen in dogs. In dogs, the lesions predominantly concern the white matter of the cerebrum (Störk et al., 2019).

Breed: Schnauzer, Standard (Dog) (VBO_0201189).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: