Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608884 (gene) , 618797 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2023

Molecular basis: Christen et al. (2023) identified a likely causal variant in Belgian shepherd dogs: "Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7)."

Clinical features: Christen et al. (2023) "investigated a [Belgian shepherd] litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. ... Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype."

Pathology: Christen et al. (2023): "Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells [in affected Belgian shepherds]."

Prevalence: Christen et al. (2023): "Genotyping a cohort of almost 900 Belgian shepherd dogs [for the ~4.8 kb deletion] showed ... a carrier frequency of 5% in the population."

Breed: Belgian Shepherd Dog (Dog) (VBO_0200144).
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: