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

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 123695 (gene) , 608940 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific name: Skeletal dysplasia 3; disproportionate dwarfism

Species-specific symbol: SD3

Species-specific description: Skeletal dysplasia 3 (SD3) is a moderately severe form of disproportionate dwarfism in Vizslas. Affected dogs have short legs and their shoulder height is reduced by ~11 cm compared to non-affected dogs. Skeletal dysplasia represents a highly heterogenoues group of diseases with more than 400 distinct entitities described in humans.

Mapping: Ludwig-Peisker et al. (2022) performed linkage mapping in a single family with two affected and two unaffected offspring and homozygosity mapping in six affected dogs. The intersection of the linked and homozygous intervals resulted in two closely neighbouring segments on chromosome 33 that together spanned ~4 Mb. The exact boundaries of the critical intervals were Chr33:26,941,791-28,331,855 and Chr33:29,015,236-31,008,198 (UU_Cfam_GSD_1.0 assembly).

Molecular basis: By whole-genome resequencing of one of the affected dogs at 19.9x coverage and comparing the data to 926 control genomes, Ludwig-Peisker et al. (2022) identified a single private homozygous protein changing variant in the cirtical interval on chromosome 33. "This variant affected the PCYT1A gene encoding phosphate cytidylyltransferase 1A, choline, which has also been termed choline-phosphate cytidylyltransferase-α. The genomic variant designation is Chr33:30,067,814:g.A>G (UU_Cfam_GSD_1.0 assembly). It represents a missense variant, XM_038583131.1:c.673T>C, predicted to cause an exchange of a highly conserved amino acid in the PCYT1A protein XP_038439059.1:p.(Y225H)." The genotypes at this variant showed perfect genotype-phenotype association in a cohort of 7 cases and 123 unaffected Vizslas. However, Ludwig-Peisker et al. (2022) encountered one additional Vizsla affected by disproportional dwarfism that was homozygous for the wildtype allele at the PCYT1A variant. In contrast to the 7 other cases from the study, this dog had a marked brachygnathia inferior in addition to the short legs. Ludwig-Peisker et al. (2022) hypothesized that the phenotype in this dog may have been caused by another genetic variant and that heterogeneity provides a plausible explanation for the discordant genotype in this dog.

Clinical features: Ludwig-Peisker et al. (2022) measured shoulder heights in 29 adult Vizslas that had been genotyped for the PCYT1A:p.Y225H variant. The shoulder height in 7 homozygous mutant dogs was highly variable. On average, homozygous mutant dogs were ~11 cm shorter than dogs with at least one wildtype PCY1A allele. Ludwig-Peisker et al. (2022) found no size differences between homozygous wildtype and heterozygous dogs. Radiographs of affected dogs showed shortened and thickened radius and ulna with procurvatum and varus deformity. The humerus in an affected dog was also markedly shortened with flattened articular surfaces. Similar changes were seen in the hind limbs with marked shortening and deformity of the femur resulting in subluxation of the hip joint and secondary deformity of the acetabula. So far, no clinically overt consequences such as osteoarthritis and lameness due to the skeletal changes have been observed in the affected dogs. However, the oldest affected dog in Ludwig-Peisker et al. (2022) was only 7 years old. Human patients with PCYT1A variants are affected by spondylometaphyseal dysplasia with cone-rod dystrophy and develop an early-onset progressive visual impairment associated with a pigmentary maculopathy and cone-rod dysfunction. The ophthalmologic examination of a single affected Vizsla at seven years of age did not reveal any signs of cone-rod dystrophy (Ludwig-Peisker et al. 2022).

Breed: Vizsla (Dog) (VBO_0201389).
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: