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

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 604042 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Renamed from 'Chondrodysplasia, disproportionate short-limbed' to 'Chondrodysplasia, disproportionate short-limbed, ITGA10-related' [11/06/2024]

History: This specific type of chondrodysplasia was first reported by Bingel and Sande (1982) in Norwegian Elkhounds.

Inheritance: Kyöstilä et al. (2013) provided strong evidence of autosomal recessive inheritance.

Mapping: By conducting a GWAS on nine affected and nine control Norwegian Elkhounds, each genotyped with the Illumina CanineSNP20 SNP Chip (yielding 14,626 informative SNPs), Kyöstilä et al. (2013) mapped the disorder to a 2Mb region (from 60 to 62 Mb (CanFam2.0 assembly)) of chromosome CFA17, containing 33 genes.

Molecular basis: The most likely functional candidate gene in the region mapped by Kyöstilä et al. (2013) (see above) was ITAG10, encoding integrin subunit alpha 10. Sequencing all exons in this gene in two affecteds, an obligate carrier and a half-sib of an affected dog, revealed four exonic SNVs, namely three synonymous and one nonsense (c.2083C>T in exon 16; p.Arg695*) [omia.variant:336]. Widespread genotyping of the latter in families of Norwegian Elkhounds and Karelian bear dog, each segregating this disorder, indicated it to be the causal mutation.
Donner et al. (2016) "present an unexpected molecular explanation for one type of disproportionate dwarfism in the Chinook breed: an ITGA10 variant (c.2083C>T) [omia.variant:336] ... ." DNA panel screening for the varaint known to cuase disease in other breeds identified the variant in the Chinook breed and further investigation identified a chondrodysplastic Chinook dog that was homozygous for the ITGA10 variant."

Clinical features: As reported by Bingel and Sande (1982): "Radiographic changes included flaring and increased width of the distal metaphyses of the radius and ulna, delayed ossification of the cuboid bones of the carpus, and reduction in length of the vertebral bodies. The zone of chondrocyte proliferation was decreased in width and contained areas of abnormal cell column formation alternated with wide areas of matrix. Chondrocytes in all zones contained one or more inclusions bounded by a smooth discontinuous membrane. The material within the inclusions appeared homogeneous and stained blue-green with Movat's pentachrome and deep blue with alcian blue-periodic acid-Schiff at pH 1.0 and 2.6. The distribution of ruthenium red granules in the matrix frequently revealed poor differentiation into territorial and interterritorial zones".

Prevalence: As reported by Kyöstilä et al. (2013), "Carrier frequency of the c.2083C>T mutation was 24% in a cohort of 156 randomly selected Finnish NEs [Norwegian Elkhound] and 8% in a population sample of 287 KBDs [Karelian bear dog]".

Breeds: Chinook (Dog) (VBO_0200353), Karelian Bear Dog (Dog) (VBO_0200754), Norwegian Elkhound (Dog) (VBO_0200955).
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: