Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 224050 (trait) , 192977 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Dandy-Walker-like malformation; inferior cerebellar hypoplasia

Species-specific symbol: DWLM

Mapping: By conducting a GWAS involving 9 affected and 11 normal Eurasier dogs, each genotyped with the Illumina HD SNP chip (yielding 110,848 informative markers), Gerber et al. (2015) mapped this disorder to the 90.9–94.2 Mb region of canine chromosome CFA1 (CanFam 3 assembly). Subsequent homozygosity mapping confirmed this candidate region.

Molecular basis: Comparison of the whole-genome sequence of one of the affected Eurasier dogs with similar data from 47 dogs of other breeds enabled Gerber et al. (2015) to narrow the candidate field down to 4 non-synonymous variants. Genotyping of these four variants in 34 Eurasier dogs revealed only one variant that co-segregated perfectly with the disorder allele: a single bp deletion in VLDLR (c.1713delC) which "results in a frameshift and premature stop codon. It is predicted to truncate more than a third of the encoded very low density lipoprotein receptor (p.W572Gfs*10)".

Clinical features: This disorder in Eurasier dogs was described by Bernardino et al. (2015): "A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 - 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs".

Breed: Eurasier (Dog) (VBO_0200512).
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: