Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 613686 (trait) , 608059 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific symbol: SCD

Species-specific description: Also called Comma defect (Willet et al., 2015), "due to the gross anatomical shape of the abnormal pups".

Inheritance: The three-generation pedigree reported by Willet et al. (2015) was consistent with autosomal recessive inheritance, which was confirmed with genotyping of the causal mutation in the extended family of the affected dogs.

Mapping: By conducting a GWAS on a family comprising normal parents plus 3 affected and 5 normal offspring, each genotyped with the Canine HD BeadChip (yielding 73,921 informative SNPs), Willet et al. (2015) mapped this disorder to a 25 Mb region on chromosome CFA5:29.84Mb–45.26Mb.

Molecular basis: Comparative analysis by Willet et al. (2015), based on location and phenotype in the mouse, revealed 19 positional comparative candidate genes. Whole-genome sequencing of two of the affected sibs revealed 5 candidate functional mutations, which were subsequently narrowed down to the causal mutation, a "guanine deletion at CFA5:35,940,090 (CFA5:32,945,846 in canFam3.1) within exon 2 of HES7 (c.126delG) . . . [which] introduces a frameshift mutation, causing alteration from the 43rd amino acid onwards and resulting in a premature termination codon in place of the 66th amino acid (p.(Thr43ProfsTer24))". Genotyping for this mutation in 133 dogs, including the three affected dogs and extended family members, confirmed this as the causal mutation.

Clinical features: As reported by Willet et al. (2015), "The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number." Also, "The three affected pups were born stillborn or died within hours of birth. Gross external examination of the pups by the attending veterinarian revealed a reduction in body length compared with normal littermates (data not available). The hindquarters of affected pups were reduced in size compared to the forequarters, giving an overall comma-like morphology to the body". One of the affected samples had umbilical hernia and another had a cleft hard palate.

Prevalence: Willet et al. (2015) tested 127 Miniature Schnauzers and six Standard Schnauzers for the deletion. Only the three affected pups tested homozygous for the mutant allele, and four family members tested heterozygous, giving an estimated allele frequency of 0.04 for the eastern Australian population tested. Carrier imported family members from Sweden and Argentina suggest that the allele may be globally dispersed.

Breed: Miniature Schnauzer (Dog) (VBO_0200896).
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: